This phase III trial tests two hypotheses in patients with low-risk and average-risk medulloblastoma. Medulloblastoma is a type of cancer that occurs in the back of the brain. The term, risk, refers to the chance of the cancer coming back after treatment. Subjects with low-risk medulloblastoma typically have a lower chance of the cancer coming back than subjects with average-risk medulloblastoma. Although treatment for newly diagnosed average-risk and low-risk medulloblastoma is generally effective at treating the cancer, there are still concerns about the side effects of such treatment. Side effects or unintended health conditions that arise due to treatment include learning difficulties, hearing loss or other issues in performing daily activities. Standard therapy for newly diagnosed average-risk or low-risk medulloblastoma includes surgery, radiation therapy, and chemotherapy (including cisplatin). Cisplatin may cause hearing loss as a side effect. In the average-risk medulloblastoma patients, this trial tests whether the addition of sodium thiosulfate (STS) to standard of care chemotherapy and radiation therapy reduces hearing loss. Previous studies with STS have shown that it may help reduce or prevent hearing loss caused by cisplatin. In the low-risk medulloblastoma patients, the study tests whether a less intense therapy (reduced radiation) can provide the same benefits as the more intense therapy. The less intense therapy may cause fewer side effects. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of cancer cells. The overall goals of this study are to see if giving STS along with standard treatment (radiation therapy and chemotherapy) will reduce hearing loss in medulloblastoma patients and to compare the overall outcome of patients with medulloblastoma treated with STS to patients treated without STS on a previous study in order to make sure that survival and recurrence of tumor is not worsened.
PRIMARY OBJECTIVES: I. To evaluate the efficacy of sodium thiosulfate (STS) infusion administered during cisplatin-containing chemotherapy cycles (compared to a historical cohort selected from ACNS0331 which received chemotherapy without STS) in reducing hearing loss in children with newly-diagnosed average-risk medulloblastoma. II. To estimate and monitor event-free survival (EFS) in this study against a carefully selected cohort from ACNS0331 to guard against loss of efficacy due to STS. SECONDARY OBJECTIVES: I. To estimate and monitor overall survival (OS) in this study against a carefully selected control cohort from ACNS0331. II. To estimate the incidence of ototoxicity-related cisplatin dose modifications in the average-risk cohort. III. To estimate the incidence of cisplatin-related nephrotoxicity in both the average-risk and low-risk cohorts. IV. To evaluate full scale intelligence neurocognitive outcomes and trajectories of patients with average-risk medulloblastoma treated with STS compared to the control cohort from ACNS0331. V. To evaluate quality of life and psychosocial outcomes and trajectories of patients with average-risk medulloblastoma treated with STS compared to published norms. VI. To estimate and monitor EFS, OS, and patterns of recurrence in patients with low-risk features treated using a reduced craniospinal radiation approach. VII. To evaluate the trajectory of hearing loss in medulloblastoma patients treated with STS. VIII. To evaluate household material hardship as a social determinant of neurocognitive, quality of life, and psychosocial outcomes in patients with average-risk and low risk medulloblastoma. EXPLORATORY OBJECTIVES: I. To obtain paired blood and tumor tissue to be banked for future biology studies involving comprehensive molecular analysis, including but not limited to whole exome sequencing, ribonucleic acid (RNA) sequencing, and methylation. II. To bank blood and cerebrospinal fluid for future studies. III. To evaluate attention, processing speed, memory, and executive function neurocognitive outcomes and trajectories, as well as hearing-related quality of life outcomes and trajectories, of patients with average-risk medulloblastoma treated with STS. IV. To evaluate neurocognitive, quality of life, and psychosocial outcomes of patients with low-risk features treated using a reduced craniospinal radiation approach. OUTLINE: CHEMORADIOTHERAPY: Patients undergo radiation therapy 5 days per week for 6 weeks (weeks 1-6) and receive vincristine intravenously (IV) once weekly on weeks 2-7 in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Beginning 4 weeks after chemoradiotherapy, patients receive lomustine orally (PO) on day 1 of cycles 1, 2, 4, 5, 7, and 8, cisplatin IV over 6 hours on day 1 of cycles 1, 2, 4, 5, 7, and 8, sodium thiosulfate IV over 15 minutes on day 1 of cycles 1, 2, 4, 5, 7, and 8, and cyclophosphamide IV over 30-60 minutes on days 1 and 2 of cycles 3, 6, and 9. Patients also receive vincristine IV on days 1, 8, and 15 of cycles 1, 2, 4, 5, 7, and 8, and on days 1 and 8 of cycles 3, 6, and 9. Treatment repeats every 6 weeks (cycles 1, 2, 4, 5, 7 and 8) or every 4 weeks (cycles 3, 6, and 9) for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo magnetic resonance imaging (MRI) and collection of cerebrospinal fluid (CSF) throughout the study. Patients may also optionally undergo blood sample collection throughout the study. After completion of study treatment, patients are followed up every 3 months for years 1-2, every 6 months for years 3-4, and then annually for years 5-10.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
225
Ancillary studies
Ancillary studies
Undergo CSF and blood sample collection
Given IV
Given IV
Given PO
Undergo MRI
Ancillary studies
Undergo radiation therapy
Given IV
Ancillary studies
Given IV
Children's Hospital of Alabama
Birmingham, Alabama, United States
SUSPENDEDUSA Health Strada Patient Care Center
Mobile, Alabama, United States
RECRUITINGPhoenix Childrens Hospital
Phoenix, Arizona, United States
RECRUITINGArkansas Children's Hospital
Little Rock, Arkansas, United States
Percentage of patients with >= grade 2 hearing loss
Will estimate the number and percentage of patients with \>= grade 2 hearing loss using the society of pediatric oncology (SIOP) scale (defined as hearing threshold \>20 dB at \>= 4kHz) 4 weeks after the last dose of cisplatin. If hearing loss is observed in both ears, the worse ear will be used for this primary analysis.
Time frame: At 4 weeks after the last dose of cisplatin
Event-free survival (EFS)
Will estimate the EFS distribution using Kaplan-Meier (KM) method.
Time frame: From initiation of the protocol treatment to the occurrence of disease progression, disease recurrence, death from any cause, or occurrence of a second malignant neoplasm, assessed up to 10 years
Overall survival (OS)
Will calculate the OS distribution using KM method.
Time frame: Up to 10 years
Incidence of ototoxicity-related cisplatin dose modifications in the average-risk cohort
Will be calculated by dividing the total number of ototoxicity-related cisplatin dose modifications by the cumulative dose of cisplatin. Summary statistics including mean, standard deviation (SD), median and range will be used to summarize the data by cohorts.
Time frame: Up to 10 years
Incidence of cisplatin-related nephrotoxicity in both the average-risk and low-risk cohorts
The frequency of cisplatin-related nephrotoxicity including Grade 3 and higher creatinine increase, acute kidney injury, and chronic kidney disease will be calculated per patient as raw counts. Summary statistics will be reported including mean, median, standard deviation and range by cohorts.
Time frame: Up to 10 years
Full scale intelligence neurocognitive outcomes and trajectories of patients with average-risk medulloblastoma treated with sodium thiosulfate (STS)
A psychologist-administered battery will be used to assess longitudinal trajectories in the estimated full scale intelligence quotient (FSIQ) using the Wechsler Intelligence Scale Vocabulary and Block Design subtest. Box-plots will be drawn for each time point to visually look for change over time. Will estimate pairwise changes in FSIQ between 9 month and 30-month and between 9-month and 60-month measurements. Summary statistics will be provided for each time point and for each pairwise change including mean, standard deviation, median and range. Will compare FSIQ between two time points using parametric or non-parametric one-sample approaches depending on the normality of the data.
Time frame: Up to 5 years
Quality of life and psychosocial outcomes of patients with average-risk medulloblastoma treated with STS
Will compare quality of life (general) and psychosocial (adaptive, social, emotional, behavioral) outcomes from this study between baseline and post treatment as well as to the published healthy norms.
Time frame: Up to 5 years
EFS in patients with low-risk features treated using a reduced craniospinal radiation approach
KM estimates of the EFS distributions for the low-risk cohort will be provided.
Time frame: Up to 10 years
OS in patients with low-risk features treated using a reduced craniospinal radiation approach
KM estimates of the OS distributions for the low-risk cohort will be provided.
Time frame: Up to 10 years
Patterns of recurrence in patients with low-risk features treated using a reduced craniospinal radiation approach
The summary statistics such as count and frequency will be used to describe the patterns of recurrence.
Time frame: Up to 10 years
Trajectory of hearing loss medulloblastoma patients treated with STS
The number of patients with \>= Grade 2 hearing loss using the SIOP scale in the evaluable ear at each time point will be summarized along with its 95% confidence interval.
Time frame: Up to 60 months
Household material hardship as a social determinant of neurocognitive, quality of life, and psychosocial outcomes in patients with average-risk and low-risk medulloblastoma
The Household Survey will be administered to parents at various timepoints to measure household material hardship. Summary statistics will be provided for each time point including mean, standard deviation, median and range for each outcome measure of interest.
Time frame: Up to 60 months post-enrollment
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Loma Linda University Medical Center
Loma Linda, California, United States
RECRUITINGMiller Children's and Women's Hospital Long Beach
Long Beach, California, United States
RECRUITINGChildren's Hospital Los Angeles
Los Angeles, California, United States
RECRUITINGValley Children's Hospital
Madera, California, United States
RECRUITINGKaiser Permanente-Oakland
Oakland, California, United States
RECRUITINGChildren's Hospital of Orange County
Orange, California, United States
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