Trial Outcomes & Findings for Chemotherapy Followed by Radiation Therapy in Treating Younger Patients With Newly Diagnosed Localized Central Nervous System Germ Cell Tumors (NCT NCT01602666)

Last Updated: 2025-11-20

Results Overview

Binomial estimate of the 3-year PFS rate defined as "Yes" for patients who were followed up per protocol and were progression free at 3-years, and "No" for those who either experienced a progression or were lost to follow-up/withdrew from the trial within 3 years from enrollment. Progression was determined by MRI using the COG Guidelines for Measurement of Tumor Size (\>25% increase in 2D or \>40% in 3D of the product of perpendicular diameters of the target lesion) as well as by tumor marker assessments which were mandatory for this study.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

262 participants

Primary outcome timeframe

3 years

Results posted on

2025-11-20

Participant Flow

Patients enrolled on the study from 6/27/2012 to 11/1/2016 on Stratum 1 and from 6/27/2012 to 10/26/2018 on Stratum 2

There were 111 patients enrolled in Stratum 1 with localized nongerminomatous germ cell tumors (NGGCT) and 151 patients enrolled in Stratum 2 with localized CNS Germinoma (Germinoma). Of these 107 in Stratum 1 and 137 in Stratum 2 were deemed eligible for the study. This report is limited to eligible subjects.

Participant milestones

Participant milestones
Measure	Stratum 1 Localized Non-Germinomatous Germ Cell Tumors (NGGCT) Patients receive induction therapy comprising carboplatin intravenously (IV) over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3 of courses 1, 3, and 5. Patients also receive ifosfamide IV over 60 minutes and etoposide over 60-120 minutes on days 1-5 of courses 2, 4, and 6. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or PR undergo 3-dimensional conformal radiation therapy (3DRT) or intensity modulated radiation therapy (IMRT) once daily (QD) 5 days a week for 6 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients who achieve CR or PR after second-look surgery undergo 3DRT or IMRT QD 5 days a week for 6 weeks.	Stratum 2 Localized Germinoma Patients receive induction therapy comprising carboplatin IV over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients with CR or continued CR (CCR) undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients found to have fibrosis, scar, mature teratoma, or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with stable disease (SD) or PR with \> 0.5 cm (suprasellar) or \> 1 cm (pineal) but =\< 1.5 cm residual disease do not undergo second-look surgery and undergo 3DRT or IMRT QD 5 days a week for 4 weeks.
Induction Chemotherapy STARTED	107	137
Induction Chemotherapy COMPLETED	70	113
Induction Chemotherapy NOT COMPLETED	37	24
Radiation Therapy on Protocol STARTED	70	113
Radiation Therapy on Protocol Evaluable for Reduced Dose (30Gy)	66	0
Radiation Therapy on Protocol Evaluable for Reduced Dose (18 Gy)	0	74
Radiation Therapy on Protocol Evaluable for RT Dose (24Gy)	0	16
Radiation Therapy on Protocol COMPLETED	60	82
Radiation Therapy on Protocol NOT COMPLETED	10	31

Reasons for withdrawal

Reasons for withdrawal
Measure	Stratum 1 Localized Non-Germinomatous Germ Cell Tumors (NGGCT) Patients receive induction therapy comprising carboplatin intravenously (IV) over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3 of courses 1, 3, and 5. Patients also receive ifosfamide IV over 60 minutes and etoposide over 60-120 minutes on days 1-5 of courses 2, 4, and 6. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or PR undergo 3-dimensional conformal radiation therapy (3DRT) or intensity modulated radiation therapy (IMRT) once daily (QD) 5 days a week for 6 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients who achieve CR or PR after second-look surgery undergo 3DRT or IMRT QD 5 days a week for 6 weeks.	Stratum 2 Localized Germinoma Patients receive induction therapy comprising carboplatin IV over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients with CR or continued CR (CCR) undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients found to have fibrosis, scar, mature teratoma, or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with stable disease (SD) or PR with \> 0.5 cm (suprasellar) or \> 1 cm (pineal) but =\< 1.5 cm residual disease do not undergo second-look surgery and undergo 3DRT or IMRT QD 5 days a week for 4 weeks.
Induction Chemotherapy Death	2	1
Induction Chemotherapy Lack of Efficacy	16	7
Induction Chemotherapy Physician Decision	12	5
Induction Chemotherapy Withdrawal by Subject	0	2
Induction Chemotherapy Refusal of further protocol therapy	5	6
Induction Chemotherapy Radiotherapy can't be initiated in 6 wks	2	3
Radiation Therapy on Protocol Lost to Follow-up	4	5
Radiation Therapy on Protocol Withdrawal by Subject	2	3
Radiation Therapy on Protocol In-evaluable for reduced dose(30.6 Gy)	4	0
Radiation Therapy on Protocol In-evaluable for reduced dose(18 Gy)	0	14
Radiation Therapy on Protocol In-evaluable for RT dose (24Gy)	0	9

Baseline Characteristics

Chemotherapy Followed by Radiation Therapy in Treating Younger Patients With Newly Diagnosed Localized Central Nervous System Germ Cell Tumors

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Stratum 1 Localized Non-Germinomatous Germ Cell Tumors (NGGCT) n=107 Participants Patients receive induction therapy comprising carboplatin intravenously (IV) over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3 of courses 1, 3, and 5. Patients also receive ifosfamide IV over 60 minutes and etoposide over 60-120 minutes on days 1-5 of courses 2, 4, and 6. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or PR undergo 3-dimensional conformal radiation therapy (3DRT) or intensity modulated radiation therapy (IMRT) once daily (QD) 5 days a week for 6 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients who achieve CR or PR after second-look surgery undergo 3DRT or IMRT QD 5 days a week for 6 weeks.	Stratum 2 Localized Germinoma n=137 Participants Patients receive induction therapy comprising carboplatin IV over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients with CR or continued CR (CCR) undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients found to have fibrosis, scar, mature teratoma, or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with stable disease (SD) or PR with \> 0.5 cm (suprasellar) or \> 1 cm (pineal) but =\< 1.5 cm residual disease do not undergo second-look surgery and undergo 3DRT or IMRT QD 5 days a week for 4 weeks.	Total n=244 Participants Total of all reporting groups
Age, Categorical <=18 years	100 Participants	124 Participants n=4 Participants	224 Participants n=8 Participants
Age, Categorical Between 18 and 65 years	7 Participants	13 Participants n=4 Participants	20 Participants n=8 Participants
Age, Categorical >=65 years	0 Participants	0 Participants n=4 Participants	0 Participants n=8 Participants
Age, Continuous	11.0 years	14.1 years n=4 Participants	13.0 years n=8 Participants
Sex: Female, Male Female	27 Participants	37 Participants n=4 Participants	64 Participants n=8 Participants
Sex: Female, Male Male	80 Participants	100 Participants n=4 Participants	180 Participants n=8 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	20 Participants	16 Participants n=4 Participants	36 Participants n=8 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	83 Participants	113 Participants n=4 Participants	196 Participants n=8 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	4 Participants	8 Participants n=4 Participants	12 Participants n=8 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants n=4 Participants	0 Participants n=8 Participants
Race (NIH/OMB) Asian	8 Participants	14 Participants n=4 Participants	22 Participants n=8 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants	8 Participants n=4 Participants	9 Participants n=8 Participants
Race (NIH/OMB) Black or African American	6 Participants	9 Participants n=4 Participants	15 Participants n=8 Participants
Race (NIH/OMB) White	78 Participants	86 Participants n=4 Participants	164 Participants n=8 Participants
Race (NIH/OMB) More than one race	0 Participants	1 Participants n=4 Participants	1 Participants n=8 Participants
Race (NIH/OMB) Unknown or Not Reported	14 Participants	19 Participants n=4 Participants	33 Participants n=8 Participants
Region of Enrollment United States	93 participants	117 participants n=4 Participants	210 participants n=8 Participants
Region of Enrollment Australia	7 participants	10 participants n=4 Participants	17 participants n=8 Participants
Region of Enrollment Canada	7 participants	6 participants n=4 Participants	13 participants n=8 Participants
Region of Enrollment New Zealand	0 participants	4 participants n=4 Participants	4 participants n=8 Participants

PRIMARY outcome

Timeframe: 3 years

Population: Localized NGGCT treated with 30.6 Gy WVF RT + 23.4 Gy primary site boost. Patients must have had complete response (CR) or partial response (PR) to induction chemotherapy by MRI and markers; or underwent second-look surgery and were found to have mature teratoma, residual scar or fibrosis and fit the definition of CR/PR after second-look surgery.

Outcome measures

Outcome measures
Measure	Stratum 1 Localized Non-Germinomatous Germ Cell Tumors (NGGCT) n=66 Participants Patients receive induction therapy comprising carboplatin intravenously (IV) over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3 of courses 1, 3, and 5. Patients also receive ifosfamide IV over 60 minutes and etoposide over 60-120 minutes on days 1-5 of courses 2, 4, and 6. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or PR undergo 3-dimensional conformal radiation therapy (3DRT) or intensity modulated radiation therapy (IMRT) once daily (QD) 5 days a week for 6 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients who achieve CR or PR after second-look surgery undergo 3DRT or IMRT QD 5 days a week for 6 weeks.	Stratum 2 Localized Germinoma Patients receive induction therapy comprising carboplatin IV over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients with CR or continued CR (CCR) undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients found to have fibrosis, scar, mature teratoma, or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with stable disease (SD) or PR with \> 0.5 cm (suprasellar) or \> 1 cm (pineal) but =\< 1.5 cm residual disease do not undergo second-look surgery and undergo 3DRT or IMRT QD 5 days a week for 4 weeks.
3-year Progression-free Survival (PFS) Rate of Patients With Nongerminomatous Germ Cell Tumor (NGGCT) Who Were Treated With Reduced Dose Whole Ventricular-field Irradiation	83.33 percentage of patients Interval 72.13 to 91.38	—

PRIMARY outcome

Timeframe: 3 years

Population: Localized CNS Germinoma treated with dose-reduced RT (18 Gy WVI + 12 Gy primary site boost) and had complete response (CR) after induction chemotherapy by MRI and tumor marker criteria; or underwent second-look surgery and were found to have mature teratoma, residual scar or fibrosis and fit the definition of CR after second-look surgery.

Binomial estimate of the 3-year PFS rate defined as "Yes" for patients who were followed up per protocol and were progression free at 3-years, and "No" for those who either experienced a progression or were lost to follow-up/withdrew from the trial within 3 years from initiation of treatment. Progression was determined by MRI using the COG Guidelines for Measurement of Tumor Size (\>25% increase in 2D or \>40% in 3D of the product of perpendicular diameters of the target lesion) as well as by tumor marker assessments which were mandatory for this study.

Outcome measures

Outcome measures
Measure	Stratum 1 Localized Non-Germinomatous Germ Cell Tumors (NGGCT) n=74 Participants Patients receive induction therapy comprising carboplatin intravenously (IV) over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3 of courses 1, 3, and 5. Patients also receive ifosfamide IV over 60 minutes and etoposide over 60-120 minutes on days 1-5 of courses 2, 4, and 6. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or PR undergo 3-dimensional conformal radiation therapy (3DRT) or intensity modulated radiation therapy (IMRT) once daily (QD) 5 days a week for 6 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients who achieve CR or PR after second-look surgery undergo 3DRT or IMRT QD 5 days a week for 6 weeks.	Stratum 2 Localized Germinoma Patients receive induction therapy comprising carboplatin IV over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients with CR or continued CR (CCR) undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients found to have fibrosis, scar, mature teratoma, or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with stable disease (SD) or PR with \> 0.5 cm (suprasellar) or \> 1 cm (pineal) but =\< 1.5 cm residual disease do not undergo second-look surgery and undergo 3DRT or IMRT QD 5 days a week for 4 weeks.
3-year PFS Rate of Patients With Localized CNS Germinoma Who Were Treated With Reduced Dose Radiation Therapy	86.49 percentage of patients Interval 76.55 to 93.32	—

PRIMARY outcome

Timeframe: Up to 5 years

Population: All eligible patients who received the radiation therapy were included as evaluable patients for analysis.

Estimated scores for the cognitive functions of processing speed, attention/concentration, and estimated IQ were assessed using the age-appropriate version of the Wechsler Scales of Intelligence. The range for the Processing Speed Index (PSI) is 45 to 155, with a mean of 100 and a standard deviation of 15. Estimated IQ was estimated using 2 subtests from the Wechsler Scales of Intelligence to derive a standard score with a mean of 100 and standard deviation of 15 with a range of 45 to 158. Scores from the 2 subtests were summed and translated to a standard score using published procedures. Attention/concentration was measured by the Digit Span subtest score from the Wechsler Scales of Intelligence. Subset scores have a range of 1-19, with a mean of 10 and standard deviation of 3. Higher scores on all these measures indicate higher or better cognitive performance, lower scores indicate lower or worse cognitive functioning.

Outcome measures

Outcome measures
Measure	Stratum 1 Localized Non-Germinomatous Germ Cell Tumors (NGGCT) n=70 Participants Patients receive induction therapy comprising carboplatin intravenously (IV) over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3 of courses 1, 3, and 5. Patients also receive ifosfamide IV over 60 minutes and etoposide over 60-120 minutes on days 1-5 of courses 2, 4, and 6. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or PR undergo 3-dimensional conformal radiation therapy (3DRT) or intensity modulated radiation therapy (IMRT) once daily (QD) 5 days a week for 6 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients who achieve CR or PR after second-look surgery undergo 3DRT or IMRT QD 5 days a week for 6 weeks.	Stratum 2 Localized Germinoma n=113 Participants Patients receive induction therapy comprising carboplatin IV over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients with CR or continued CR (CCR) undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients found to have fibrosis, scar, mature teratoma, or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with stable disease (SD) or PR with \> 0.5 cm (suprasellar) or \> 1 cm (pineal) but =\< 1.5 cm residual disease do not undergo second-look surgery and undergo 3DRT or IMRT QD 5 days a week for 4 weeks.
Neurocognitive Function Using the ALTE07C1 Protocol Attention/Concentration at 9 months	9.4 Standardized Scores Interval 8.6 to 10.3	10.0 Standardized Scores Interval 9.3 to 10.7
Neurocognitive Function Using the ALTE07C1 Protocol Attention/Concentration at 30 months	10.1 Standardized Scores Interval 9.1 to 11.1	9.8 Standardized Scores Interval 9.0 to 10.6
Neurocognitive Function Using the ALTE07C1 Protocol Attention/Concentration at 60 months	9.3 Standardized Scores Interval 8.3 to 10.4	10.2 Standardized Scores Interval 9.1 to 11.3
Neurocognitive Function Using the ALTE07C1 Protocol Estimated IQ at 9 months	94.3 Standardized Scores Interval 90.0 to 98.7	99.0 Standardized Scores Interval 95.9 to 102.1
Neurocognitive Function Using the ALTE07C1 Protocol Estimated IQ at 30 months	101.3 Standardized Scores Interval 96.2 to 106.4	102.9 Standardized Scores Interval 99.1 to 106.7
Neurocognitive Function Using the ALTE07C1 Protocol Estimated IQ at 60 months	97.3 Standardized Scores Interval 91.2 to 103.5	104.5 Standardized Scores Interval 100.0 to 108.9
Neurocognitive Function Using the ALTE07C1 Protocol Processing Speed at 9 months	90.1 Standardized Scores Interval 85.2 to 94.9	91.8 Standardized Scores Interval 88.3 to 95.3
Neurocognitive Function Using the ALTE07C1 Protocol Processing Speed at 30 months	93.4 Standardized Scores Interval 87.7 to 99.0	95.6 Standardized Scores Interval 92.3 to 98.9
Neurocognitive Function Using the ALTE07C1 Protocol Processing Speed at 60 months	90.1 Standardized Scores Interval 82.2 to 98.0	97.5 Standardized Scores Interval 93.1 to 101.9

SECONDARY outcome

Timeframe: Up to 3 years

Kaplan Meier estimate of the 3-year PFS is provided. PFS is the time interval measured from enrollment until progression or death from any cause or until last follow-up for those who were event free at the time of analysis. Patients who were lost to follow-up or withdrew consent were censored in this analysis. Progression was determined by MRI using the COG Guidelines for Measurement of Tumor Size (\>25% increase in 2D or \>40% in 3D of the product of perpendicular diameters of the target lesion) as well as by tumor marker assessments which were mandatory for this study.

Outcome measures

Outcome measures
Measure	Stratum 1 Localized Non-Germinomatous Germ Cell Tumors (NGGCT) n=66 Participants Patients receive induction therapy comprising carboplatin intravenously (IV) over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3 of courses 1, 3, and 5. Patients also receive ifosfamide IV over 60 minutes and etoposide over 60-120 minutes on days 1-5 of courses 2, 4, and 6. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or PR undergo 3-dimensional conformal radiation therapy (3DRT) or intensity modulated radiation therapy (IMRT) once daily (QD) 5 days a week for 6 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients who achieve CR or PR after second-look surgery undergo 3DRT or IMRT QD 5 days a week for 6 weeks.	Stratum 2 Localized Germinoma Patients receive induction therapy comprising carboplatin IV over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients with CR or continued CR (CCR) undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients found to have fibrosis, scar, mature teratoma, or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with stable disease (SD) or PR with \> 0.5 cm (suprasellar) or \> 1 cm (pineal) but =\< 1.5 cm residual disease do not undergo second-look surgery and undergo 3DRT or IMRT QD 5 days a week for 4 weeks.
Estimation of the PFS Distribution of Patients With NGGCT Treated With Involved-field Radiation Therapy (IFR)	87.88 percentage of patients Interval 77.22 to 93.75	—

SECONDARY outcome

Timeframe: Up to 3 years

Kaplan Meier estimate of the 3-year overall survival (OS) is provided. OS is the time interval measured from enrollment until death from any cause or until last follow-up for those who were alive at the time of analysis. Patients who were lost to follow-up or withdrew consent were censored in this analysis.

Outcome measures

Outcome measures
Measure	Stratum 1 Localized Non-Germinomatous Germ Cell Tumors (NGGCT) n=66 Participants Patients receive induction therapy comprising carboplatin intravenously (IV) over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3 of courses 1, 3, and 5. Patients also receive ifosfamide IV over 60 minutes and etoposide over 60-120 minutes on days 1-5 of courses 2, 4, and 6. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or PR undergo 3-dimensional conformal radiation therapy (3DRT) or intensity modulated radiation therapy (IMRT) once daily (QD) 5 days a week for 6 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients who achieve CR or PR after second-look surgery undergo 3DRT or IMRT QD 5 days a week for 6 weeks.	Stratum 2 Localized Germinoma Patients receive induction therapy comprising carboplatin IV over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients with CR or continued CR (CCR) undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients found to have fibrosis, scar, mature teratoma, or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with stable disease (SD) or PR with \> 0.5 cm (suprasellar) or \> 1 cm (pineal) but =\< 1.5 cm residual disease do not undergo second-look surgery and undergo 3DRT or IMRT QD 5 days a week for 4 weeks.
Estimation of the Overall Survival (OS) Distribution of Patients With NGGCT Treated With IFR Assessed	92.42 percentage of patients Interval 82.75 to 96.78	—

SECONDARY outcome

Timeframe: Up to 3 years

Population: The eligible patients with localized germinoma and CSF serum hCGbeta of 50 mIU/mL or less or CSF serum hCGbeta greater than 50 mIU/mL and less than or equal to 100 mIU/mL.

Kaplan Meier estimate of the 3-year PFS rate is provided. PFS is the time interval measured from initiation of treatment until progression or death from any cause or until last follow-up for those who were event free at the time of analysis. Patients who were lost to follow-up or withdrew consent were censored in this analysis. Progression was determined by MRI using the COG Guidelines for Measurement of Tumor Size (\>25% increase in 2D or \>40% in 3D of the product of perpendicular diameters of the target lesion) as well as by tumor marker assessments which were mandatory for this study.

Outcome measures

Outcome measures
Measure	Stratum 1 Localized Non-Germinomatous Germ Cell Tumors (NGGCT) n=131 Participants Patients receive induction therapy comprising carboplatin intravenously (IV) over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3 of courses 1, 3, and 5. Patients also receive ifosfamide IV over 60 minutes and etoposide over 60-120 minutes on days 1-5 of courses 2, 4, and 6. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or PR undergo 3-dimensional conformal radiation therapy (3DRT) or intensity modulated radiation therapy (IMRT) once daily (QD) 5 days a week for 6 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients who achieve CR or PR after second-look surgery undergo 3DRT or IMRT QD 5 days a week for 6 weeks.	Stratum 2 Localized Germinoma n=6 Participants Patients receive induction therapy comprising carboplatin IV over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients with CR or continued CR (CCR) undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients found to have fibrosis, scar, mature teratoma, or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with stable disease (SD) or PR with \> 0.5 cm (suprasellar) or \> 1 cm (pineal) but =\< 1.5 cm residual disease do not undergo second-look surgery and undergo 3DRT or IMRT QD 5 days a week for 4 weeks.
Estimation of the PFS Distribution of Patients With Localized Germinoma Patients and Cerebrospinal Fluid (CSF) Serum hCGbeta of 50 mIU/mL or Less or CSF Serum hCGbeta Greater Than 50 mIU/mL and Less Than or Equal to 100 mIU/mL	93.26 percentage of patients Interval 86.95 to 96.58	80.00 percentage of patients Interval 20.38 to 96.92

SECONDARY outcome

Timeframe: Up to 3 years

Population: The eligible patients with localized germinoma and CSF serum hCGbeta of 50 mIU/mL or less or CSF serum hCGbeta greater than 50 mIU/mL and less than or equal to 100 mIU/mL

Kaplan Meier estimate of the 3-year overall survival (OS) is provided for each group. OS is the time interval measured from enrollment until death from any cause or until last follow-up for those who were alive at the time of analysis. Patients who were lost to follow-up or withdrew consent were censored in this analysis.

Outcome measures

Outcome measures
Measure	Stratum 1 Localized Non-Germinomatous Germ Cell Tumors (NGGCT) n=131 Participants Patients receive induction therapy comprising carboplatin intravenously (IV) over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3 of courses 1, 3, and 5. Patients also receive ifosfamide IV over 60 minutes and etoposide over 60-120 minutes on days 1-5 of courses 2, 4, and 6. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or PR undergo 3-dimensional conformal radiation therapy (3DRT) or intensity modulated radiation therapy (IMRT) once daily (QD) 5 days a week for 6 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients who achieve CR or PR after second-look surgery undergo 3DRT or IMRT QD 5 days a week for 6 weeks.	Stratum 2 Localized Germinoma n=6 Participants Patients receive induction therapy comprising carboplatin IV over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients with CR or continued CR (CCR) undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients found to have fibrosis, scar, mature teratoma, or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with stable disease (SD) or PR with \> 0.5 cm (suprasellar) or \> 1 cm (pineal) but =\< 1.5 cm residual disease do not undergo second-look surgery and undergo 3DRT or IMRT QD 5 days a week for 4 weeks.
Estimation of the OS Distribution of Patients With Localized Germinoma Patients and CSF Serum hCGbeta of 50 mIU/mL or Less or CSF Serum hCGbeta Greater Than 50 mIU/mL and Less Than or Equal to 100 mIU/mL	98.38 percentage of patients Interval 93.69 to 99.59	100 percentage of patients Interval 100.0 to 100.0

Adverse Events

Stratum 1 Localized Non-Germinomatous Germ Cell Tumors (NGGCT)

Serious events: 5 serious events

Other events: 84 other events

Deaths: 13 deaths

Stratum 2 Localized Germinoma

Serious events: 1 serious events

Other events: 107 other events

Deaths: 2 deaths

Serious adverse events

Serious adverse events
Measure	Stratum 1 Localized Non-Germinomatous Germ Cell Tumors (NGGCT) n=107 participants at risk Patients receive induction therapy comprising carboplatin intravenously (IV) over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3 of courses 1, 3, and 5. Patients also receive ifosfamide IV over 60 minutes and etoposide over 60-120 minutes on days 1-5 of courses 2, 4, and 6. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or PR undergo 3-dimensional conformal radiation therapy (3DRT) or intensity modulated radiation therapy (IMRT) once daily (QD) 5 days a week for 6 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients who achieve CR or PR after second-look surgery undergo 3DRT or IMRT QD 5 days a week for 6 weeks.	Stratum 2 Localized Germinoma n=137 participants at risk Patients receive induction therapy comprising carboplatin IV over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients with CR or continued CR (CCR) undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with normalization of markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery. Patients found to have fibrosis, scar, mature teratoma, or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with stable disease (SD) or PR with \> 0.5 cm (suprasellar) or \> 1 cm (pineal) but =\< 1.5 cm residual disease do not undergo second-look surgery and undergo 3DRT or IMRT QD 5 days a week for 4 weeks.
Blood and lymphatic system disorders Anemia	0.00% 0/107 • From initiation of induction of therapy to the date of last follow-up, approximately 3 years. For most subjects the adverse events were observed while on active treatment or shortly thereafter. Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.	0.73% 1/137 • Number of events 1 • From initiation of induction of therapy to the date of last follow-up, approximately 3 years. For most subjects the adverse events were observed while on active treatment or shortly thereafter. Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.
Blood and lymphatic system disorders Febrile neutropenia	0.93% 1/107 • Number of events 1 • From initiation of induction of therapy to the date of last follow-up, approximately 3 years. For most subjects the adverse events were observed while on active treatment or shortly thereafter. Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.	0.73% 1/137 • Number of events 1 • From initiation of induction of therapy to the date of last follow-up, approximately 3 years. For most subjects the adverse events were observed while on active treatment or shortly thereafter. Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.
Nervous system disorders Headache	0.93% 1/107 • Number of events 1 • From initiation of induction of therapy to the date of last follow-up, approximately 3 years. For most subjects the adverse events were observed while on active treatment or shortly thereafter. Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.	0.00% 0/137 • From initiation of induction of therapy to the date of last follow-up, approximately 3 years. For most subjects the adverse events were observed while on active treatment or shortly thereafter. Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.
Nervous system disorders Hydrocephalus	0.93% 1/107 • Number of events 1 • From initiation of induction of therapy to the date of last follow-up, approximately 3 years. For most subjects the adverse events were observed while on active treatment or shortly thereafter. Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.	0.00% 0/137 • From initiation of induction of therapy to the date of last follow-up, approximately 3 years. For most subjects the adverse events were observed while on active treatment or shortly thereafter. Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.
Nervous system disorders Intracranial hemorrhage	0.93% 1/107 • Number of events 1 • From initiation of induction of therapy to the date of last follow-up, approximately 3 years. For most subjects the adverse events were observed while on active treatment or shortly thereafter. Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.	0.00% 0/137 • From initiation of induction of therapy to the date of last follow-up, approximately 3 years. For most subjects the adverse events were observed while on active treatment or shortly thereafter. Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.93% 1/107 • Number of events 1 • From initiation of induction of therapy to the date of last follow-up, approximately 3 years. For most subjects the adverse events were observed while on active treatment or shortly thereafter. Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.	0.00% 0/137 • From initiation of induction of therapy to the date of last follow-up, approximately 3 years. For most subjects the adverse events were observed while on active treatment or shortly thereafter. Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.
Infections and infestations Sepsis	0.93% 1/107 • Number of events 1 • From initiation of induction of therapy to the date of last follow-up, approximately 3 years. For most subjects the adverse events were observed while on active treatment or shortly thereafter. Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.	0.00% 0/137 • From initiation of induction of therapy to the date of last follow-up, approximately 3 years. For most subjects the adverse events were observed while on active treatment or shortly thereafter. Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.

Other adverse events

Additional Information

Results Reporting Coordinator

Children's Oncology Group

Phone: 626 447-0064

Email: [email protected]

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