Clinical trial NCT01878617: A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma
Official title: A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Medulloblastoma
Keywords: SJMB12
Brain Cancer
Brain Tumors in Children
Cisplatin
Cyclophosphamide
Embryonal Tumors of CNS
GDC-0449
Gemcitabine
Hedgehog Pathway Inhibitor
Infratentorial
Mass in Brain
Medulloblastoma
Medulloblastoma Brain Tumor
Medulloblastoma Tumor
Molecular
Neuroectodermal Tumor, Primitive
Newly Diagnosed Childhood Medulloblastoma
Non-SHH Non-WNT
Pediatric Brain Tumor
Pemetrexed
Posterior Fossa Tumor
Proton Beam Therapy
Radiation Therapy
Rare Brain Tumor
Risk
SHH
Sonic Hedgehog Pathway
St Jude Medullo
St. Jude Brain Tumor Studies
St. Jude Medullo
St. Jude Studies
St. Jude Treatment
Treatment for Brain Tumors in Children
Untreated Childhood Medulloblastoma
Vincristine
Vismodegib
WNT
Lead sponsor: St. Jude Children's Research Hospital
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
name: National Cancer Institute (NCI)
First posted: 2013-06-17
Enrollment: 660
Sex: ALL
Minimum age (years): 3
Maximum age (years): 39
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Historically, medulloblastoma treatment has been determined by the amount of leftover disease present after surgery, also known as clinical risk (standard vs. high risk). Recent studies have shown that medulloblastoma is made up of distinct molecular subgroups which respond differently to treatment. This suggests that clinical risk alone is not adequate to identify actual risk of recurrence. In order to address this, we will stratify medulloblastoma treatment in this phase II clinical trial based on both clinical risk (low, standard, intermediate, or high risk) and molecular subtype (WNT, SHH, or Non-WNT Non-SHH). This stratified clinical and molecular treatment approach will be used to evaluate the following:

* To find out if participants with low-risk WNT tumors can be treated with a lower dose of radiation to the brain and spine, and a lower dose of the chemotherapy drug cyclophosphamide while still achieving the same survival rate as past St. Jude studies with fewer side effects.
* To find out if adding targeted chemotherapy after standard chemotherapy will benefit participants with SHH positive tumors.
* To find out if adding new chemotherapy agents to the standard chemotherapy will improve the outcome for intermediate and high risk Non-WNT Non-SHH tumors.
* To define the cure rate for standard risk Non-WNT Non-SHH tumors treated with reduced dose cyclophosphamide and compare this to participants from the past St. Jude study.

All participants on this study will have surgery to remove as much of the primary tumor as safely possible, radiation therapy, and chemotherapy. The amount of radiation therapy and type of chemotherapy received will be determined by the participant's treatment stratum. Treatment stratum assignment will be based on the tumor's molecular subgroup assignment and clinical risk.

The participant will be assigned to one of three medulloblastoma subgroups determined by analysis of the tumor tissue for tumor biomarkers:

* WNT (Strata W): positive for WNT biomarkers
* SHH (Strata S): positive for SHH biomarkers
* Non-WNT Non-SHH, Failed, or Indeterminate (Strata N): negative for WNT and SHH biomarkers or results are indeterminable

Participants will then be assigned to a clinical risk group (low, standard, intermediate, or high) based on assessment of:

* How much tumor is left after surgery
* If the cancer has spread to other sites outside the brain \[i.e., to the spinal cord or within the fluid surrounding the spinal cord, called cerebrospinal fluid (CSF)\]
* The appearance of the tumor cells under the microscope
* Whether or not there are chromosomal abnormalities in the tumor, and if present, what type (also called cytogenetics analysis)

Detailed description: Primary Objectives:

* To estimate the progression free survival distribution of WNT-medulloblastoma patients treated on Stratum W1 with reduced-dose craniospinal irradiation and reduced-dose cyclophosphamide.
* To estimate progression-free survival distribution of Non-WNT Non-SHH medulloblastoma patients treated on Stratum N1 with reduced dose cyclophosphamide.
* To estimate the progression free survival distribution of skeletally mature SHH medulloblastoma patients assigned to Stratum S1 and treated with oral maintenance therapy using a targeted SHH pathway inhibitor (vismodegib) after the adjuvant chemotherapy regimen is complete and to compare the outcome to molecularly and clinically matched historical controls from SJMB03 as well as outcome from other published cohorts.
* To evaluate the effect of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on cardiopulmonary fitness.
* To assess the impact of a computer-based working memory intervention (administered prophylactically at the end of chemotherapy), relative to standard of care, on a performance-based measure of working memory.

Secondary Objectives:

* To estimate overall survival distribution of WNT-medulloblastoma patients treated on Stratum W1 with reduced-dose craniospinal irradiation and reduced-dose cyclophosphamide and compare progression free and overall survival distributions to molecularly and clinically matched historical controls from St. Jude SJMB03 study.
* To estimate the progression free (in S1 skeletally immature and S2 both sub-strata) and overall survival distributions of SHH medulloblastoma patients enrolled on Strata S1 and S2 some of whom will be treated with oral maintenance therapy using a targeted SHH pathway inhibitor (vismodegib) after adjuvant chemotherapy regimen is complete and compare these outcomes to molecularly and clinically matched historical controls from SJMB03 as well as outcome from other published cohorts.
* To estimate the progression free and overall survival distributions of Non-WNT Non-SHH medulloblastoma patients treated on Strata N2 and N3 with 3 cycles of pemetrexed and gemcitabine in addition to 4 cycles of conventional adjuvant chemotherapy and compare the progression-free and overall survival distributions to molecularly and clinically matched historical controls from St. Jude SJMB03 study separately for each stratum.
* To estimate the overall survival distribution of Non-WNT Non-SHH medulloblastoma patients treated on Stratum N1 with reduced dose cyclophosphamide and compare progression free and overall survival distributions to molecularly and clinically matched historical controls from St. Jude SJMB03 study.
* To evaluate the feasibility and toxicity of adding pemetrexed and gemcitabine to adjuvant chemotherapy regimen of intermediate and high risk Non-WNT Non-SHH medulloblastoma patients (Strata N2 and N3).
* To evaluate the feasibility and toxicity of oral maintenance therapy with the targeted SHH inhibitor (vismodegib) after conventional adjuvant chemotherapy regimen is complete.
* To estimate the cumulative incidence of local disease failure at 2 and 5 years based on treatment regimen, strata, and clinical and treatment factors.
* To evaluate the effects of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on physical performance, fatigue, health related quality of life, memory, attention and executive function at the end of the intervention, at the end of adjuvant chemotherapy, and one, two and five years off adjuvant chemotherapy, among children treated for medulloblastoma.
* To evaluate the impact of an aerobic training intervention on sleep quality and quantity in children with medulloblastoma.
* To evaluate the relation between baseline cognitive performance and the variables of sleep quality and quantity, and fatigue in children with medulloblastoma.
* To estimate change in neurocognitive performance using a comprehensive assessment battery (e.g., measures of intellectual function, academic abilities, attention, memory, processing speed and executive functions) and investigate the relationship of change to relevant demographic factors (e.g., gender, age at treatment, time since treatment and socioeconomic status) and clinical factors (e.g., treatment intensity/risk group, posterior fossa syndrome).
* To assess the impact of a computer-based working memory intervention, relative to standard of care, on additional performance- and rater-based measures of attention, processing speed and executive functions.
* To compare the impact of a computer-based working memory intervention in conjunction with an aerobic training intervention, relative to either intervention in isolation, on measures of attention, processing speed and executive functions.
* To evaluate the maintenance of improvements on measures of attention, working memory, processing speed and executive functions six months following participation in the computer-based working memory intervention program.

Outline: This is a multicenter study. Patients are stratified according to molecular subgroup assignment (WNT, SHH, or Non-WNT Non- SHH) and then by clinical risk stratification (extent of resection, M stage, histologic subtype, and cytogenetic features). All patients will be treated with risk-adapted radiation therapy and adjuvant chemotherapy. Patients assigned to Stratum W1 will receive reduced dose radiation therapy. Patients assigned to Stratum W2, S1, N1, or N2 will receive standard dose radiation therapy. Patients assigned to Stratum W3, S2, or N3 will receive high dose radiation therapy. Radiation therapy will be followed by 4 cycles of adjuvant conventional chemotherapy with cyclophosphamide, cisplatin and vincristine for all patients. Patients assigned to Stratum N2 or N3 (Non-WNT Non-SHH with high risk factors) will receive 3 additional cycles of pemetrexed and gemcitabine chemotherapy intermixed into the conventional adjuvant chemotherapy cycles. Patients with SHH subtype (Stratum S1 or S2) who are skeletally mature will receive 12 months additional maintenance therapy with vismodegib.

Patients may consent to provide tumor tissue, blood, and CSF samples for biological studies. Tumor tissues are analyzed for the activation of the WNT signaling pathway, activation of the SHH signaling pathway, validation of novel patterns of gene expression via immunohistochemical (IHC) analysis; validation of genetic abnormalities via interphase fluorescence in situ hybridization (iFISH); construction of gene expression profiles via microarray analysis; construction of DNA methylation profiling via microarrays; single nucleotide polymorphism (SNP) analysis for DNA copy number aberrations; potential oncogenes and tumor suppressor genes via DNA sequence analysis; expression of a number of cell signal proteins implicated in the biology of medulloblastoma via western blot; expression of additional proteins encoded by genes associated through SNP and gene expression array analysis with clinical disease behavior. Blood samples are analyzed from patients whose tumors contain gene mutations via sequence analysis of constitutional DNA. CSF and blood samples are analyzed for identification of potential tumor markers. Parents may consent to have blood samples analyzed for inheritable gene mutations associated with medulloblastoma.

Patients may also consent to exploratory research that include additional functional MRI imaging to investigate damage to neural connections from therapy; additional psychological testing to identify neurocognitive effects of therapy; additional heart and lung testing to identify treatment effects; additional endocrine studies to identify treatment effect on growth and development.

After completion of study treatment, patients are followed every 6 months for 5 years.

Eligibility criteria: INCLUSION CRITERIA

* Medulloblastoma or medulloblastoma variants including posterior fossa PNET as documented by an institutional pathologist.
* Participant's age meets one of the following: (1) Age greater than or equal to 3 years and less than 22 years of age at the time of diagnosis (may enroll on Strata W, S or N), OR (2) age is greater than or equal to 22 years and less than 40 years AND patient has SHH medulloblastoma (must enroll on Stratum S).
* No previous radiotherapy, chemotherapy or other brain tumor directed therapy other than corticosteroid therapy and surgery.
* Patients must begin treatment as outlined in the protocol within 36 days of definitive surgery (day of surgery is day 0; definitive surgery includes second surgeries to resect residual tumor).
* Adequate performance status: children \< 10-Lansky Score ≥ 30; children ≥ 10-Karnofsky ≥ 30 (except for posterior fossa syndrome).
* Females of child-bearing potential cannot be pregnant or breast-feeding. Female participants \> 10 years of age or post-menarche must have a negative serum or urine pregnancy test prior to enrollment.
* Biological parent(s) of participant (child) enrolling on this protocol. These parents will be assigned to cohort P. The exclusion criteria below do not apply to this cohort.

EXCLUSION CRITERIA

* CNS embryonal tumor other than medulloblastoma or PNET in the posterior fossa, for example, patients with diagnosis of Atypical Teratoid / Rhabdoid Tumor (ATRT), supratentorial PNET, pineoblastoma, ependymoblastoma, ETANTR are excluded.
* Research participants with other clinically significant medical disorders that could compromise their ability to tolerate protocol therapy or would interfere with the study procedures or results history.

Participants in the Stratum S maintenance chemotherapy portion of the study must meet the criteria below prior to start of vismodegib therapy:

* Participants must be Stratum S (SHH)
* Participants must be skeletally mature defined as females with a bone age ≥ 15 years and males with a bone age ≥ 17 years.
* Must be able to swallow pills
* BSA must be \>0.67 and \<2.5 m2
* Male and female participants of reproductive potential must agree to effective contraception during and after study treatment. See Appendices I and II for further guidance for participants receiving vismodegib
* ANC ≥ 1000/mm\^3 (after G-CSF discontinued)
* Platelets ≥ 50,000/mm\^3 (without support)
* Hgb ≥ 8 g/dL (with or without transfusion support)
* Serum creatinine ≤ 1.5 mg/dL
* Total bilirubin ≤ 1.5X the institutional ULN
* SGPT (ALT) ≤ 2.5X the institutional ULN
* SGOT (AST) ≤ 2.5X the institutional ULN
* Alkaline Phosphatase ≤ 1.5X the institutional ULN
* Serum albumin ≥ 2.5 g/dL

Participants in the exercise intervention portion of the study must meet all criteria below:

* Must be ≥ 5 years and \< 22 years at the time of enrollment
* Must have no congenital heart disease
* Must be capable of performing the exercise intervention at the time of baseline assessment as determined by the treating physician.

Participants in the cognitive remediation intervention portion of the study must meet all criteria below:

* Completed protocol-directed radiation therapy
* ≥5 years at the time of remediation intervention consent or age is greater than or equal to 22 years and less than 40 years and patient has SHH medulloblastoma
* English as primary language and training aide who speaks English available to participate in required sessions
* No significant cognitive impairment operationalized as either an IQ \< 70 for children with St. Jude SJMB12 study baseline testing or based on clinician judgment baseline IQ missing
* No major sensory or motor impairment that would preclude valid cognitive testing (e.g., unresolved posterior fossa syndrome, blindness, poorly controlled seizures/photosensitive epilepsy, psychosis) or a major psychological condition that would preclude completion of the intervention (e.g., significant oppositionality, autism spectrum disorder, severe anxiety or depressive symptoms)

Primary outcomes:
measure: Progression-free Survival in Stratum W1
timeFrame: 2 years after diagnosis
measure: Progression-free Survival in Stratum N1
timeFrame: 2 years after diagnosis
measure: Progression-free Survival in Stratum S1 Skeletally Mature Cohort
timeFrame: 2 years after diagnosis
measure: Change in VO2 Peak Value
timeFrame: baseline and 12 weeks post-randomization
measure: Change in Spatial Span Backward Standard Score
timeFrame: baseline and 10-12 weeks post baseline
Secondary outcomes:
measure: Progression-free Survival in Stratum W1 Compared to Historical Controls
timeFrame: 2 years after diagnosis
measure: Overall Survival in Stratum W1
timeFrame: 2 years after diagnosis
measure: Progression-free Survival in Stratum S1 Skeletally Immature Cohort
timeFrame: 2 years after diagnosis
measure: Progression-free Survival in Stratum S2 Skeletally Mature Cohort
timeFrame: 2 years after diagnosis
measure: Progression-free Survival in Stratum S2 Skeletally Immature Cohort
timeFrame: 2 years after diagnosis
measure: Overall Survival in Stratum S1 Skeletally Mature Cohort
timeFrame: 2 years after diagnosis
measure: Overall Survival in Stratum S1 Skeletally Immature Cohort
timeFrame: 2 years after diagnosis
measure: Overall Survival in Stratum S2 Skeletally Mature Cohort
timeFrame: 2 years after diagnosis
measure: Overall Survival in Stratum S2 Skeletally Immature Cohort
timeFrame: 2 years after diagnosis
measure: Progression-free Survival in Stratum N2
timeFrame: 2 years after diagnosis
measure: Overall Survival in Stratum N2
timeFrame: 2 years after diagnosis
measure: Progression-free Survival in Stratum N3
timeFrame: 2 years after diagnosis
measure: Overall Survival in Stratum N3
timeFrame: 2 years after diagnosis
measure: Progression-free Survival in Stratum N1 Compared to Historical Controls
timeFrame: 2 years after diagnosis
measure: Overall Survival in Stratum N1
timeFrame: 2 years after diagnosis
measure: Percentage of Participants Who Complete Pemetrexed and Gemcitabine Therapy
timeFrame: 10 months after on treatment
measure: Percentage of Participants Who Complete Vismodegib Therapy
timeFrame: 20 months after on treatment
measure: Number of Local Failures
timeFrame: 2 and 5 years after on treatment
measure: Change in hand grip strength
timeFrame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment
measure: Change in range of motion
timeFrame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment
measure: Change in overall flexibility
timeFrame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment
measure: Change in motor proficiency
timeFrame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment
measure: Change in quality of life (QOL) score
timeFrame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment
measure: Change in fatigue score
timeFrame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment
measure: Change in measure of memory function
timeFrame: Baseline (at enrollment), 12 weeks, and at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3).
measure: Change in measure of attention
timeFrame: Baseline (at enrollment), 12 weeks, and at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3).
measure: Change in executive function score
timeFrame: Baseline (at enrollment), 12 weeks, and at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3).
measure: Change in sleep
timeFrame: Baseline and 10-12 weeks post randomization
measure: Association between baseline cognitive performance and sleep quality
timeFrame: Baseline and approximately 7-10 months after treatment
measure: Association between baseline cognitive performance and sleep quantity
timeFrame: Baseline and approximately 7-10 months after treatment
measure: Association between baseline cognitive performance and fatigue
timeFrame: Baseline and approximately 7-10 months after treatment
measure: Longitudinal change in measure of intellectual function
timeFrame: Baseline through 5 years after enrollment
measure: Association of demographic and clinical factors with change in intellectual function
timeFrame: Baseline through 5 years after enrollment
measure: Longitudinal change in measure of academic ability
timeFrame: Baseline through 5 years after enrollment
measure: Association of demographic and clinical factors with change in academic ability
timeFrame: Baseline through 5 years after enrollment
measure: Longitudinal change in measure of attention
timeFrame: Baseline through 5 years after enrollment
measure: Association of demographic and clinical factors with change in attention
timeFrame: Baseline through 5 years after enrollment
measure: Longitudinal change in measure of memory
timeFrame: Baseline through 5 years after enrollment
measure: Association of demographic and clinical factors with change in memory
timeFrame: Baseline through 5 years after enrollment
measure: Longitudinal change in measure of cognitive processing speed function
timeFrame: Baseline through 5 years after enrollment
measure: Association of demographic and clinical factors with change in cognitive processing speed
timeFrame: Baseline through 5 years after enrollment
measure: Longitudinal change in measure of neurocognitive executive function
timeFrame: Baseline through 5 years after enrollment
measure: Association of demographic and clinical factors with change in neurocognitive executive function
timeFrame: Baseline through 5 years after enrollment
measure: Change in measure of attention
timeFrame: Baseline (at 7-10 months after start of therapy) and at 3 months after baseline
measure: Change in measure of processing speed
timeFrame: Baseline (at 7-10 months after start of therapy) and at 3 months after baseline
measure: Change in measure of executive function ability
timeFrame: Baseline (at 7-10 months after start of therapy) and at 3 months after baseline
measure: Change in measure of attention among 3 groups (working memory intervention + physical exercise intervention VS. working memory intervention alone VS. physical training intervention alone)
timeFrame: Baseline and at 3 months after baseline
measure: Change in measure of processing speed among 3 groups (working memory intervention + physical exercise intervention VS. working memory intervention alone VS. physical training intervention alone)
timeFrame: Baseline and at 3 months after baseline
measure: Change in measure of executive function among 3 groups (working memory intervention + physical exercise intervention VS. working memory intervention alone VS. physical training intervention alone)
timeFrame: Baseline and at 3 months after baseline
measure: Change in measure of attention between participants who received computer-based intervention VS. those who did not
timeFrame: Baseline (at 7-10 months after on treatment) through 6 months after baseline.
measure: Change in measure of working memory between participants who received computer-based intervention VS. those who did not
timeFrame: Baseline (at 7-10 months after on treatment) through 6 months after baseline.
measure: Change in measure of processing speed between participants who received computer-based intervention VS. those who did not
timeFrame: Baseline (at 7-10 months after on treatment) through 6 months after baseline.
measure: Change in measure of executive function between participants who received computer-based intervention VS. those who did not
timeFrame: Baseline (at 7-10 months after on treatment) through 6 months after baseline.
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Lucille Packard Children's Hospital at Stanford University Medical Center
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Orlando
country: United States
facility: Arnold Palmer Hospital for Children
state: Florida
city: Minneapolis
country: United States
facility: Children's Hospital and Clinics of Minnesota
state: Minnesota
city: Durham
country: United States
facility: Duke Children's Hospital and Health Center
state: North Carolina
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: Texas Children's Cancer Center
state: Texas
city: Randwick
country: Australia
facility: Sydney Children's Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Children's Hospital at Westmead
state: New South Wales
city: Brisbane
country: Australia
facility: Queensland Children's Hospital
state: Queensland
city: Melbourne
country: Australia
facility: Royal Children's Hospital, Melbourne
state: Victoria
city: Perth
country: Australia
facility: Perth Children's Hospital
state: Western Australia
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier Universitaire Sainte-Justine
state: Quebec
city: Auckland
country: New Zealand
facility: Starship Children's Hospital
Study officials:
affiliation: St. Jude Children's Research Hospital
name: Amar Gajjar, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Jude Children's Research Hospital
name: Giles Robinson, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Khan RB, Patay Z, Klimo P, Huang J, Kumar R, Boop FA, Raches D, Conklin HM, Sharma R, Simmons A, Sadighi ZS, Onar-Thomas A, Gajjar A, Robinson GW. Clinical features, neurologic recovery, and risk factors of postoperative posterior fossa syndrome and delayed recovery: a prospective study. Neuro Oncol. 2021 Sep 1;23(9):1586-1596. doi: 10.1093/neuonc/noab030.