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3-Dimensional Conformal Radiation Therapy

Intensity-Modulated Radiation Therapy

Ute K Bartels

This phase II trial studies how well chemotherapy followed by radiation therapy work in treating younger patients with newly diagnosed central nervous system germ cell tumors that have not spread to other parts of the brain, spinal canal, or body (localized). Drugs used as chemotherapy, such as carboplatin, etoposide, and ifosfamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x rays to kill tumor cells. Giving chemotherapy followed by radiation therapy may kill more tumor cells.

PRIMARY OBJECTIVES:

I. To determine, as measured by the 3-year progression-free survival (PFS) rate and patterns of failure, whether dose and volume of irradiation can be safely reduced to 30.6 Gy whole ventricular-field irradiation (WVI) plus 23.4 Gy primary site boost instead of 36 Gy craniospinal irradiation (CSI) plus primary site boost in the subgroup of children and young adults (ages 3 to =\< 21 years) with localized nongerminomatous germ cell tumor (NGGCT) who have a magnetic resonance imaging (MRI) and tumor marker criteria (cerebrospinal fluid \[CSF\] and serum) for confirmed complete response (CR) or partial response (PR) to induction chemotherapy and negative serum and cerebrospinal fluid (CSF) tumor markers OR in patients who have less than a PR after induction chemotherapy with negative tumor markers who undergo a second-look surgery and are found to have only mature teratoma, residual scar or fibrosis and fit the definition of CR/PR after second-look surgery.

II. To determine, as measured by the 3-year PFS rate and patterns of failure, whether simplified chemotherapy followed by dose-reduced radiation therapy is effective for treating children and young adults (ages 3 to =\< 21 years) with localized primary central nervous system (CNS) germinoma who present with serum and/or CSF human chorionic gonadotropin-beta (hCGbeta) =\< 50 mIU/mL.

III. To prospectively evaluate and longitudinally model the cognitive, social, and behavioral functioning of children and young adults who are treated with reduced radiation dose and volume of irradiation in Stratum 1 (NGGCT) and with dose-reduced radiation therapy in Stratum 2 (germinoma) using the ALTE07C1 protocol.

SECONDARY OBJECTIVES:

I. To estimate the PFS and overall survival (OS) distributions of patients with NGGCT treated with 30.6 Gy WVI and involved-field radiation therapy (IFR) focal boost to 54 Gy.

II. To estimate the PFS and OS distributions of localized germinoma patients who present with a) serum and/or CSF hCGbeta =\< 50 mIU/mL and b) serum and/or CSF hCGbeta \> 50 mIU/mL and =\< 100 mIU/mL.

OUTLINE:

STRATUM I (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 II (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.

After completion of study treatment, patients are followed up at 3, 6, and 9 months, every 4 months for 24 months, 30 months, 36 months, and then annually for up to 60 months.

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

Phase 2 Trial of Response-Based Radiation Therapy for Patients With Localized Central Nervous System Germ Cell Tumors (CNS GCT)

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.

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.

Estimated scores for processing speed, attention/concentration, and estimated IQ at 9 months, 30 months and 60 months, separately for children and young adults who are treated with reduced radiation dose and volume of irradiation in Stratum 1 (NGGCT) and with dose-reduced radiation therapy in Stratum 2 (germinoma).

Estimated change over these three timepoints for processing speed, attention/concentration, and estimated IQ, separately for children and young adults who are treated with reduced radiation dose and volume of irradiation in Stratum 1 (NGGCT) and with dose-reduced radiation therapy in Stratum 2 (germinoma).

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.

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.

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.

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.

National Cancer Institute (NCI)

Children's Oncology Group

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.

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 1 Localized Non-Germinomatous Germ Cell Tumors (NGGCT)

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.

Stratum 2 Localized Germinoma

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Australia

Canada

New Zealand

Region of Enrollment

Results Reporting Coordinator

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.

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

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.

3-year PFS Rate of Patients With Localized CNS Germinoma Who Were Treated With Reduced Dose Radiation Therapy

Neurocognitive Function Using the ALTE07C1 Protocol

Estimation of the PFS Distribution of Patients With NGGCT Treated With Involved-field Radiation Therapy (IFR)

Estimation of the Overall Survival (OS) Distribution of Patients With NGGCT Treated With IFR Assessed

hCGbeta <= 50 mIU/mL

50 mIU/mL \< CSF /serum hCGbeta \<= 100 mIU/mL

50 mIU/mL < hCGbeta <= 100 mIU/mL

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.

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

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

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Chemotherapy Followed by Radiation Therapy in Treating Younger Patients With Newly Diagnosed Localized Central Nervous System Germ Cell Tumors	NCT01602666	Central Nervous... Childhood Centr...	3-Dimensional C... Carboplatin Etoposide Ifosfamide Intensity-Modul...	3 Years - 21 Years	Children's Oncology Group
A Study of a New Way to Treat Children and Young Adults With a Brain Tumor Called NGGCT	NCT04684368	Central Nervous... Choriocarcinoma Embryonal Carci... Immature Terato... Malignant Terat... Mixed Germ Cell... Pineal Region G... Pineal Region I... Pineal Region Y... Suprasellar Ger...	Biospecimen Col... Carboplatin Etoposide Filgrastim Ifosfamide Magnetic Resona... Mesna Pegfilgrastim Peripheral Bloo... Questionnaire A... Radiation Thera... Radiation Thera... Second-Look Sur... Thiotepa	3 Years - 29 Years	Children's Oncology Group

Spots Global Cancer Trial Database for central nervous system nongerminomatous germ cell tumor