Combination Chemotherapy Followed By Peripheral Stem Cell Transplant in Treating Young Patients With Newly Diagnosed Supratentorial Primitive Neuroectodermal Tumors or High-Risk Medulloblastoma

Medulloblastoma Clinical Trial

Official title:

A Phase III Randomized Trial for the Treatment of Newly Diagnosed Supratentorial PNET and High Risk Medulloblastoma in Children < 36 Months Old With Intensive Induction Chemotherapy With Methotrexate Followed by Consolidation With Stem Cell Rescue vs. the Same Therapy Without Methotrexate

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00336024
• Other study ID #: ACNS0334
• Secondary ID: NCI-2009-00338CD
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: August 6, 2007
• Est. completion date: December 31, 2028

Study information

• Verified date: September 2023
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized phase III trial is studying two different combination chemotherapy regimens to compare how well they work in treating young patients with newly diagnosed supratentorial primitive neuroectodermal tumors or high-risk medulloblastoma when given before additional intense chemotherapy followed by peripheral blood stem cell rescue. It is not yet known which combination chemotherapy regimen is more effective when given before a peripheral stem cell transplant in treating supratentorial primitive neuroectodermal tumors or medulloblastoma.

Description:

PRIMARY OBJECTIVES:

I. To determine if treatment of infants with high risk primitive neuroectodermal tumors (PNET) central nervous system (CNS) tumors with intensive chemotherapy plus high-dose methotrexate and peripheral blood stem cell rescue results in a higher complete response rate then the same regimen without methotrexate.

SECONDARY OBJECTIVES:

I. To determine whether biologic characterization of these tumors will refine therapeutic stratification separating atypical teratoid rhabdoid tumors (AT/RT) from primitive neuroectodermal tumors (PNETs) and possibly identifying other markers of value for stratification within the group of PNETs.

II. To determine if event free survival (EFS) and patterns of failure differ between the methotrexate arm versus the arm without methotrexate.

III. To compare the acute, chronic and late effects of these two very intensive regimens, especially as to the tolerance of the same consolidation regimen following the differing induction regimens.

IV. To compare the gastrointestinal and nutritional toxicities of these intense regimens.

V. To describe and compare the quality of life outcomes and neuropsychological effects of these intense systemic therapies.

OUTLINE: Patients are randomized to 1 of 2 treatment arms

INDUCTION THERAPY:

ARM I: Patients receive vincristine IV over 1 minute on days 1, 8, and 15; etoposide IV over 1 hour on days 1-3; cyclophosphamide IV over 1 hour on days 1 and 2; cisplatin IV over 6 hours on day 3; and filgrastim (G-CSF) IV or subcutaneously (SC) beginning on day 4 and continuing until blood counts recover. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive vincristine IV over 1 minute on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or orally (PO) every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Once methotrexate levels are in a safe range, patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Patients also receive G-CSF IV or SC beginning 24 hours after the completion of chemotherapy and continuing until blood counts recover. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

In both arms, patients with stable disease or partial response after induction therapy proceed to second-look surgery followed by consolidation therapy. Patients with a complete response after induction therapy proceed directly to consolidation therapy.

CONSOLIDATION THERAPY: Beginning no more than 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous peripheral blood stem cells (PBSC) IV on day

4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up periodically for 4 years and then annually thereafter.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 91
• Est. completion date: December 31, 2028
• Est. primary completion date: December 31, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 2 Years

Eligibility

Inclusion Criteria:

• High-risk medulloblastoma defined by any of the following:

• > 1.5 cm^2 residual disease for any medulloblastoma histology, or

• Lumbar cerebral spinal fluid (CSF) cytology positive for tumor cells by analysis of fluid collected either before definitive surgery or at least 10 days after definitive surgery unless contraindicated, or

• Magnetic resonance imaging (MRI) evidence of M2 or M3 metastatic disease, or

• M4 disease

• Supratentorial primitive neuroectodermal tumor (PNET) (any M-stage) will be eligible for study entry

• Children less than 8 months of age at the time of definitive surgery with or without measurable radiographic residual tumor with M0 stage medulloblastoma will be eligible for study entry

• Patients with anaplastic medulloblastoma are eligible regardless of M-stage or residual tumor

• Patients with M0 classic, non-desmoplastic medulloblastoma (R1) with radiographically measurable residual disease < 1.5 cm^2 are eligible

• Cranial MRI (with and without gadolinium) must be done pre-operatively; post-operatively, cranial MRI (with and without gadolinium) must be done, preferably within 48 hours of surgery; entire spinal MRI must be obtained either pre-operatively (with gadolinium) or post-operatively (at least 10 days following surgery) prior to study enrollment (with and without gadolinium); patients with MRI evidence of spinal disease are eligible for this study

• Evaluation of lumbar CSF cytology (cytospin preparation for microscopic evaluation) must be performed either pre-operatively or at least 10 days after definitive surgery unless contraindicated

• Patient must have a life expectancy > 8 weeks

• Patient must have received no prior radiation therapy or chemotherapy other than corticosteroids; corticosteroids are allowable for all patients

• Creatinine clearance or radioisotope glomerular filtration rate >= 60 mL/min

• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age, and

• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamic pyruvic transaminase (SGPT) (alanine transaminase [ALT]) < 2 x ULN for age

• Shortening fraction >= 27% by echocardiogram, or

• Ejection fraction >= 47% by radionuclide angiogram

• No evidence of dyspnea at rest

• Pulse oximetry > 94% on room air

• Peripheral absolute neutrophil count (ANC) > 1,000/uL

• Platelet count > 100,000/uL (transfusion independent)

• Hemoglobin greater than 8 g/dL (may have received red blood cell [RBC] transfusions allowed)

• Hold trimethoprim/sulfamethoxazole (Bactrim) on the day of high-dose methotrexate (HDMTX) infusion and continue to hold until the methotrexate level is less than 0.1 micromolar (1 x 10-7 M)

• Avoid probenecid, penicillins, cephalosporins, aspirin, proton pump inhibitors and nonsteroidal anti-inflammatory drug (NSAIDS) on the day of methotrexate and continue until the methotrexate level is less than 0.1 micromolar (1 x 10-7 M) as renal excretion of methotrexate is inhibited by these agents

• Avoid IV contrast media, urinary acidifiers, phenytoin, and fosphenytoin on the day of methotrexate and until the methotrexate level is less than 0.1 micromolar (1 x 10-7 M)

• Concurrent use of enzyme inducing anticonvulsants (e.g. phenytoin, phenobarbital, and carbamazepine) should be avoided

• Clinically significant drug interactions have been reported when using vincristine with strong cytochrome P450 (CYP450) family 3 subfamily A member 4 (3A4) inhibitors and inducers; selected strong inhibitors of cytochrome P450 3A4 include azole antifungals, such as fluconazole, voriconazole, itraconazole, ketoconazole, and strong inducers include drugs such as rifampin, phenytoin, phenobarbitol, carbamazepine, and St. John's wort; the use of these drugs should be avoided with vincristine

• All patients and/or their parents or legal guardians must sign a written informed consent

• All institutional, Food and Drug administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Related Conditions & MeSH terms

• Anaplastic Medulloblastoma
• Medulloblastoma
• Neoplasms
• Neuroectodermal Tumors
• Neuroectodermal Tumors, Primitive
• Supratentorial Embryonal Tumor, Not Otherwise Specified
• Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor

Intervention

Procedure:
• Autologous Hematopoietic Stem Cell Transplantation
Undergo autologous PBSC resuce

Drug:
• Carboplatin
Given IV
• Cisplatin
Given IV
• Cyclophosphamide
Given IV
• Etoposide
Given IV

Biological:
• Filgrastim
Given IV or SC

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Leucovorin Calcium
Given IV or orally
• Methotrexate
Given IV

Other:
• Quality-of-Life Assessment
Ancillary studies

Drug:
• Thiotepa
Given IV
• Vincristine Sulfate
Given IV

Locations

Country	Name	City	State
Australia	Royal Children's Hospital	Parkville	Victoria
Australia	Princess Margaret Hospital for Children	Perth	Western Australia
Australia	Sydney Children's Hospital	Randwick	New South Wales
Australia	The Children's Hospital at Westmead	Westmead	New South Wales
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario
Canada	Kingston Health Sciences Centre	Kingston	Ontario
Canada	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec
Canada	The Montreal Children's Hospital of the MUHC	Montreal	Quebec
Canada	Children's Hospital of Eastern Ontario	Ottawa	Ontario
Canada	Centre Hospitalier Universitaire de Quebec	Quebec
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	British Columbia Children's Hospital	Vancouver	British Columbia
Canada	CancerCare Manitoba	Winnipeg	Manitoba
Puerto Rico	San Jorge Children's Hospital	San Juan
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Texas Tech University Health Sciences Center-Amarillo	Amarillo	Texas
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Tufts Children's Hospital	Boston	Massachusetts
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Vermont and State Agricultural College	Burlington	Vermont
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	Novant Health Presbyterian Medical Center	Charlotte	North Carolina
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Prisma Health Richland Hospital	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Driscoll Children's Hospital	Corpus Christi	Texas
United States	Medical City Dallas Hospital	Dallas	Texas
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Dayton Children's Hospital	Dayton	Ohio
United States	Kaiser Permanente Downey Medical Center	Downey	California
United States	Michigan State University Clinical Center	East Lansing	Michigan
United States	Inova Fairfax Hospital	Falls Church	Virginia
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Broward Health Medical Center	Fort Lauderdale	Florida
United States	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida
United States	Lee Memorial Health System	Fort Myers	Florida
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	Greenville Cancer Treatment Center	Greenville	South Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	Ascension Saint Vincent Indianapolis Hospital	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	Kalamazoo Center for Medical Studies	Kalamazoo	Michigan
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	East Tennessee Childrens Hospital	Knoxville	Tennessee
United States	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada
United States	Nevada Cancer Research Foundation NCORP	Las Vegas	Nevada
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Miller Children's and Women's Hospital Long Beach	Long Beach	California
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Norton Children's Hospital	Louisville	Kentucky
United States	Covenant Children's Hospital	Lubbock	Texas
United States	Valley Children's Hospital	Madera	California
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Loyola University Medical Center	Maywood	Illinois
United States	Nicklaus Children's Hospital	Miami	Florida
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	NYU Winthrop Hospital	Mineola	New York
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	Morristown Medical Center	Morristown	New Jersey
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Tulane University Health Sciences Center	New Orleans	Louisiana
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Advocate Children's Hospital-Oak Lawn	Oak Lawn	Illinois
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital of Orange County	Orange	California
United States	AdventHealth Orlando	Orlando	Florida
United States	Arnold Palmer Hospital for Children	Orlando	Florida
United States	Nemours Children's Clinic - Orlando	Orlando	Florida
United States	Nemours Children's Hospital	Orlando	Florida
United States	Orlando Health Cancer Institute	Orlando	Florida
United States	Saint Joseph's Regional Medical Center	Paterson	New Jersey
United States	Nemours Children's Clinic - Pensacola	Pensacola	Florida
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Legacy Emanuel Children's Hospital	Portland	Oregon
United States	Legacy Emanuel Hospital and Health Center	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Naval Medical Center - Portsmouth	Portsmouth	Virginia
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Sutter Medical Center Sacramento	Sacramento	California
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Medical Center-Parnassus	San Francisco	California
United States	Memorial Health University Medical Center	Savannah	Georgia
United States	Seattle Children's Hospital	Seattle	Washington
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	Overlook Hospital	Summit	New Jersey
United States	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington
United States	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida
United States	Mercy Children's Hospital	Toledo	Ohio
United States	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio
United States	New York Medical College	Valhalla	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	Saint Mary's Hospital	West Palm Beach	Florida
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Patients Who Have Either a Complete Response (CR) Rate or No Complete Response Rate	At the end of consolidation, the number of evaluable patients treated with intensive chemotherapy with methotrexate who achieved CR or not will be compared to those who achieved CR or not after treated with the same intensive chemotherapy without methotrexate. The CR rates between these two groups will be compared at a significance level of 0.1 using one-sided Chi-square test. Complete Response (CR) requires: CR for target lesions: disappearance of all target lesions, CR for non-target lesions: disappearance of all non-target lesions and no new lesions. No CR is any response not fitting the definition of CR.	At the end of consolidation treatment
Secondary	Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort	The number of patients will be reported for this analysis by Molecular Sub-types of MB, CNS-PNETs/EBTs	At baseline
Secondary	Percentage of Participants With Event Free Survival (EFS)	EFS was defined as time from enrollment to the occurrence of first event (disease progression/relapse, secondary malignancy, death from any cause) or date of last contact for patients who are event-free. The percentage of participants with EFS and 90% confidence interval were provided. The difference in incidence for the two treatment regimens were compared using a one-sided log-rank test with a significance level of 0.1.	Baseline to up to 5 years
Secondary	Patterns of Failure	The patterns of failure for relapse/disease progression will be provided for patients treated with/without methotrexate drug in three categories, namely local, distant, and both local and distant. The number of patients with each type of failure will be listed per arm. The two groups will be compared to determine if the pattern of failure distribution is different between the two arms using Fisher exact test.	Baseline to up to 5 years
Secondary	Percentage of Participants With Any Acute Adverse Events	Event is defined as the first occurrence of any acute toxicity. Estimates will be obtained using life-table methods. Patients who have progression or recurrence of disease will be censored in this analysis. Difference in incidence for the two treatment regimens will be compared using log-rank test.	Beginning of treatment to the end of consolidation
Secondary	Number of Participants With Acute Hearing Loss and No Acute Hearing Loss	Per protocol, hearing was assessed pretreatment and at regular specified intervals during treatment and off therapy, using DPOAE, audiogram or Brainstem Evoked Auditory. Per CTCAE V4.0 grade 3 Hearing impaired is defined as follows; Pediatric (on a 1,2,3,4, 6 and 8 kHz audiogram): hearing loss sufficient to indicate therapeutic intervention, including hearing aids, threshold shift >20 dB at 3 kHz and above in at least one ear, additional speech-language related services as indicated. Per CTCAE V4.0 grade 4 Hearing impaired is defined as follows; Pediatric Audiologic indication for cochlear implant and additional speech-language related services as indicated.	Beginning of treatment to the end of consolidation
Secondary	Number of Participants With Chronic Primary Hypothyroidism/Subclinical Compensatory HypothyroidismHypothyroidism/Subclinical Compensatory Hypothyroidism	Thyroid function was assessed as per ACNS0334 Endocrine Guidelines. "Normal" and "Abnormal" are defined at each institution by the laboratory standards where the blood tests are run. Primary Hypothyroidism/Subclinical Compensatory Hypothyroidism is defined as patients with Free T4 level less than "Institutional" Normal or equal to "Institutional" Normal with TSH level greater than "Institutional" Normal.	Off-treatment up to 9 years
Secondary	Number of Participants With Chronic Central Hypothyroidism	Thyroid function was assessed as per ACNS0334 Endocrine Guidelines. "Normal" and "Abnormal" are defined at each institution by the laboratory standards where the blood tests are run. Central Hypothyroidism is defined as Free T4 level less than "Institutional" Normal with TSH less than or equal to "Institutional" Normal.	Off-treatment up to 9 years
Secondary	Number of Participants With Chronic Low Somatomedin C	Low Somatomedin C is defined as patients with somatomedin C value less than institutional normal. As numbers are too small, descriptive statistics such as number will be reported for this analysis. Growth hormone function was assessed as per ACNS0334 Endocrine Guidelines. Low Somatomedin C levels are defined at each institution by the laboratory standards where the blood tests are run.	Off-treatment up to 9 years
Secondary	Number of Participants With Chronic Diabetes Insipidus	The number of patients who had "Diabetes Insipidus" and on DDAVP will be reported for this analysis due to small numbers..	Beginning of off-treatment to up to 9 years
Secondary	Number of Participants With Secondary Malignancies	The number of patients who had secondary malignancy will be reported for this analysis due to small numbers.	Off-treatment up to 9 years
Secondary	Number of Participants With Chronic/Late Hearing Loss and No Chronic/Late Hearing Loss	The number of patients who are reported to have abnormal hearing, graded according to CTCAE 4.0 or not, with onset while on therapy or when off therapy which persisted after off therapy will be reported and will be compared using Fisher exact test.	Off-treatment up to 9 years
Secondary	Rates of Gastrointestinal Toxicities	Rates of gastrointestinal toxicities reported as Adverse Events during therapy for each cycle will be summarized using standard descriptive methods (such as number of patients). The difference in number of patients with gastrointestinal toxicities between the two treatment regimens will be compared using a Chi-square test.	Beginning of treatment to the end of consolidation
Secondary	Rates of Nutritional Toxicities	Rates of nutritional toxicities reported as Adverse Events during therapy for each cycle will be summarized using standard descriptive methods (such as number of patients). The difference in number of patients with nutritional toxicities between the two treatment regimens will be compared using a Chi-square test.	Beginning of treatment to the end of consolidation
Secondary	Median/Range of Patients for Total Quality of Life (QOL) Score, Intelligence Quotient (IQ) and Processing Speed Index (PSI).	Three tools are used to assess intelligence (IQ) depending on age. The range of IQ scores is 40-160 (mean=100, SD=15); range for the Processing Speed Index (PSI)=45-155. Higher scores represent better functioning. (1) Wechsler Preschool and Primary Scale of Intelligence-4th Edition (WPPSI-IV) is used for ages 2.5 to 6 years. Bug Search and Cancellation subtests are summed to calculate PSI. (2) Wechsler Intelligence Scales for Children-5th Edition (WISC-V) is used for ages 6 - 16 years. Symbol Search and Coding subtests are summed to calculate PSI. (3) Wechsler Adult Intelligence Scales-4th Edition (WAIS-IV) is used for ages 16 and older. Symbol Search and Coding subtests are summed to calculate PSI.; The Pediatric Quality of Life Inventory Version 4 (PedsQL) measures health-related quality of life (QOL). Parents complete the measure for children ages 2-17, and patients > 18 complete a self-report version. Total scores range from 0-100, with higher scores representing better QOL.	60 months (+/- 3 months)