PRIMARY OBJECTIVES:
I. To monitor outcome to ensure that children and young adults with localized central nervous system (CNS) non-germinomatous germ cell tumors (NGGCT) treated with induction chemotherapy followed by response evaluation and whole ventricular + spinal canal irradiation (WVSCI) will maintain the excellent 2-year progression free survival (PFS) rate as compared to ACNS0122 (NCT00047320).
II. To improve disease control by decreasing the number of spinal relapses for patients who achieve a complete response (CR) or partial response (PR) and receive WVSCI as compared to whole ventricular radiation on ACNS1123 (NCT01602666).
SECONDARY OBJECTIVES:
I. To estimate the response rates to induction chemotherapy and WVSCI for localized NGGCT patients who achieve a CR/PR.
II. To estimate the PFS and overall survival (OS) for localized NGGCT patients who achieve a CR/PR and receive WVSCI.
III. To estimate the PFS and OS for patients with less than a CR/PR following Induction who subsequently receive high-dose chemotherapy with peripheral stem cell rescue (HDCSCR).
IV. To estimate the response rate for patients with less than a CR/PR following Induction who subsequently receive HDCSCR.
EXPLORATORY OBJECTIVES:
I. To prospectively compare outcomes based on radiation modality, photon versus proton, including cognitive, social and behavioral functioning, auditory, and neuro-endocrine function.
II. To compare spinal column growth and cell counts following radiation as measured by height and weight, and complete blood count (CBC) values during and after radiation therapy, based on treatment modality (photon versus \[vs.\] proton therapy) and planned inclusion/exclusion of the vertebral body in patients \< 13 years of age.
III. To compare local vs. central review recommendations for second-look surgery and document barriers for performing such surgeries as well as their clinical benefit in pediatric NGGCT.
IV. To prospectively evaluate and longitudinally model the cognitive, social, and behavioral functioning of children and young adults with localized CNS NGGCT with testing as per the Children's Oncology Group (COG) Standardized Neuropsychological and Behavioral Battery.
V. To evaluate patterns of disease recurrence/failure with respect to radiation dose distribution.
OUTLINE:
INDUCTION CHEMOTHERAPY: Patients receive carboplatin intravenously (IV) over 15-60 minutes on day 1 and etoposide IV over 90-120 minutes on days 1-3 of cycles 1, 3, and 5. Patients also receive ifosfamide IV over 60 minutes and etoposide IV over 60-120 minutes on days 1-5 of cycles 2, 4, and 6. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Patients are assigned to 1 of 2 plans (ventricular + spinal canal irradiation \[WVSCI\] or high-dose chemotherapy with peripheral stem cell rescue \[HDCSCR\]) based on response to induction chemotherapy:
* Patients who achieve radiographic CR/PR with marker normalization proceed to WVSCI. Patients who achieve radiographic CR without marker normalization proceed to HDCSCR.
* Patients who achieve less than radiographic CR/PR with marker normalization proceed to second-look surgery (unless contraindicated). If second-look surgery reveals mature teratoma or non-viable tumor, proceed to WVSCI. If second-look surgery reveals viable tumor, proceed to HDCSCR. Patients who are unable to undergo second-look surgery are removed from protocol therapy but remain on study for follow-up.
* Patients who achieve less than radiographic CR/PR without marker normalization proceed to second-look surgery (unless contraindicated). Patients then proceed to HDCSCR regardless of whether or not a second-look surgery is performed.
* Patients who achieve radiographic PR without marker normalization proceed to second-look surgery (unless contraindicated). Patients then proceed to HDCSCR regardless of whether or not a second-look surgery is performed.
PLAN A (WVSCI THERAPY): Within 6 weeks of the end of induction chemotherapy or second-look surgery, patients undergo WVSCI once daily (QD) for 5 days weekly (17 fractions followed by a boost dose for 13 fractions) for 6 weeks in the absence of disease progression or unacceptable toxicity.
PLAN B (CONSOLIDATION THERAPY \[HDCSCR\]): Within 6-8 weeks of the end of induction chemotherapy or second-look surgery, patients receive etoposide IV and thiotepa IV over 3 hours on days -5 to -3 and undergo peripheral blood stem cell (PBSC) transplant on day 0. Patients then undergo radiation therapy QD for 5 days weekly (20 fractions followed by a boost dose for 10 fractions) for 6 weeks in the absence of disease progression or unacceptable toxicity.
Patients also undergo magnetic resonance imaging (MRI), as well as collection of cerebral spinal fluid (CSF) and blood sample throughout the trial.
After completion of study treatment, patients are followed for up to 10 years.
Inclusion Criteria:
- Patients must be >= 3 years and < 30 years at the time of study enrollment
- Patients must be newly diagnosed with localized primary CNS NGGCT of the suprasellar
and/or pineal region by pathology and/or serum or cerebrospinal fluid (CSF) elevation
of AFP above institutional normal or > 10 ng/mL or human chorionic gonadotropin (hCG)
beta > 100 mIU/mL as confirmed by Rapid Central Marker Screening Review on
APEC14B1-CNS. Suprasellar, pineal and bifocal tumors are included. (CSF tumor markers
and cytology must be within 31 days prior to enrollment and start of protocol therapy
[repeat if necessary]. Serum tumor markers, AFP and hCGbeta must be within 7 days
prior to enrollment and start of protocol therapy [repeat if necessary]). Basal
ganglia or other primary sites are excluded
- Patients with any of the following pathological elements are eligible: endodermal
sinus (yolk sac), embryonal carcinoma, choriocarcinoma, malignant/immature teratoma
and mixed germ cell tumor (GCT) (i.e., may include some pure germinoma) if malignant
elements listed above are present. Patients with only mature teratoma are excluded.
Patients with pure germinoma admixed with mature teratoma are excluded (would be
eligible for pure germinoma protocols)
- Patients must have a cranial MRI with and without gadolinium at diagnosis/prior to
enrollment. If surgical resection is performed, patients must have pre-operative and
post operative brain MRI with and without gadolinium. The post operative brain MRI
should be obtained within 72 hours of surgery. If patient has a biopsy only,
post-operative brain MRI is recommended but not required (within 31 days prior to
study enrollment and start of protocol therapy )
- Patients must have a spine MRI with gadolinium obtained at diagnosis/prior to
enrollment. Spine MRI with and without gadolinium is recommended (within 31 days prior
to study enrollment and start of protocol therapy)
- Lumbar CSF must be obtained prior to study enrollment unless medically
contraindicated. If a patient undergoes surgery and lumbar CSF cytology cannot be
obtained at the time of surgery, then it should be performed at least 10 days
following surgery and prior to study enrollment. False positive cytology can occur
within 10 days of surgery
- Patients must have RAPID CENTRAL TUMOR MARKER REVIEW CSF tumor markers obtained prior
to enrollment unless medically contraindicated. Ventricular CSF obtained at the time
of CSF diversion procedure (if performed) is acceptable for tumor markers but lumbar
CSF is preferred. In case CSF diversion and biopsy/surgery are combined, CSF tumor
markers should be collected first
- Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to
enrollment)
- Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to
enrollment)
- Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days
prior to enrollment)
- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows (within 7 days
prior to enrollment):
- Age: Maximum serum creatinine (mg/dL)
- 3 to < 6 years: 0.8 (male), 0.8 (female)
- 6 to < 10 years: 1 (male), 1 (female)
- 10 to < 13 years: 1.2 (male), 1.2 (female)
- 13 to < 16 years: 1.5 (male), 1.4 (female)
- >= 16 years: male (1.7), 1.4 (female)
- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to
enrollment)
- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135
U/L (within 7 days prior to enrollment)
- Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the
value of 45 U/L
- Central nervous system function defined as:
- Patients with seizure disorder may be enrolled if on anticonvulsants and well
controlled
- Patients must not be in status epilepticus, coma or assisted ventilation prior to
study enrollment
- Protocol therapy must begin within 31 calendar days of definitive surgery or clinical
diagnosis, whichever is later. If a biopsy only was performed, the biopsy date will be
considered the date of definitive surgery. For patients who have a biopsy or
incomplete resection at diagnosis followed by additional surgery, the date of the last
resection will be considered the date of definitive surgery.
- 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
- NEUROCOGNITIVE FUNCTION AND QUALITY OF LIFE ASSESSMENT:
- English-, Spanish-, or French- speaking
- Note: Patients who speak a language other than English, Spanish, or French will
be allowed to participate in ACNS2021 but will not complete the neurocognitive
and quality of life assessments
- No known history of neurodevelopmental disorder prior to diagnosis of NGGCT (e.g.,
Down syndrome, fragile X, William syndrome, intellectual disability). Patients with
NF1 will be allowed to participate
- Additional eligibility criteria for the COG Standardized Neuropsychological Battery
only: must be at a site that has a psychologist to administer the battery
- Note: If not eligible for the COG Standardized Battery, patients should still
complete the Behavior Rating Inventory of Executive Function, Second Edition
(BRIEF-2), Pediatric Quality of Life Inventory (PedsQL), Adaptive Behavior
Assessment System Third Edition (ABAS-3), and Behavior Assessment System for
Children, Third Edition (BASC-3) questionnaires
Exclusion Criteria:
- Patients with tumors located outside the ventricles (i.e., basal ganglia, thalamus)
- Patients with only mature teratoma and non-elevated markers upon tumor sampling at
diagnosis
- Patients who have received any prior tumor-directed therapy for their diagnosis of
NGGCT other than surgical intervention and corticosteroids
- Patients with metastatic disease (i.e., MRI evaluation, lumbar CSF cytology or
intraoperative evidence of dissemination)
- Female patients who are pregnant, since fetal toxicities and teratogenic effects have
been noted for several of the study drugs
- Note: Serum and urine pregnancy tests may be falsely positive due to
HCGbeta-secreting germ cell tumors. Ensure the patient is not pregnant by
institutional standards
- Lactating females who plan to breastfeed their infants
- Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation
