A Phase II Trial Evaluating Chemotherapy Followed by Response-Based Reduced Radiation Therapy for Patients With Central Nervous System Germinomas
Summary
This phase II trial studies how well lower dose radiotherapy after chemotherapy (Carboplatin \& Etoposide) works in treating children with central nervous system (CNS) germinomas. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of tumor cells. Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and DNA repair and may kill cancer cells. Researchers want to see if lowering the dose of standard radiotherapy (RT) after chemotherapy can help get rid of CNS germinomas with fewer long-term side effects.
Detailed description
PRIMARY OBJECTIVE: I. To determine whether 12 Gy whole ventricular irradiation (WVI) and 12 Gy tumor boost would maintain similar efficacy compared to ACNS1123 stratum 2 as measured by event-free survival (EFS) in eligible patients with localized primary central nervous system (CNS) germinoma who present with serum and/or cerebrospinal fluid (CSF) human chorionic gonadotropin-beta (hCGbeta) ≤ 100 IU/L and normal alpha-fetoprotein (AFP), and meet complete response (CR) or continued complete response (CCR) criteria following chemotherapy/second-look surgery (Stratum 1). SECONDARY OBJECTIVES: I. To estimate the EFS distribution for patients with localized midline - including bifocal - CNS germinoma with partial response (PR) after chemotherapy, followed by 18 Gy WVI and 12 Gy tumor boost (Stratum 2). II. To estimate the EFS distribution for patients with localized midline - including bifocal - CNS germinoma with less than a PR after chemotherapy, followed by 24 Gy WVI and 12 Gy tumor boost (Stratum 3). III. To estimate the overall survival (OS), response rates to chemotherapy and radiotherapy (RT), as well as the patterns of failure of the various cohorts based on tumor characteristics, treatment regimen, and treatment modality. IV. To determine the impact of tumor characteristics, treatment regimen and treatment modalities on the long-term neuroendocrine function for patients with CNS germinomas. V. To prospectively evaluate processing speed of children and young adults with CNS germinoma through the Children's Oncology Group (COG) Standardized assessment battery. EXPLORATORY OBJECTIVES: I. To estimate the EFS distribution for patients with metastatic germinomas treated with chemotherapy followed by craniospinal irradiation (CSI) \[18 Gy for CR/CCR (Stratum 4)\] or \[24 Gy for less than CR (Stratum 5)\] with a 12 Gy tumor boost to the pre-treatment volume, including metastatic sites. II. To estimate the EFS distribution for patients with basal ganglia and thalamic germinomas (BGTG) treated with chemotherapy followed by whole brain irradiation (WBI) \[18 Gy for CR/CCR (Stratum 6)\] or \[24 Gy for less than CR (Stratum 7)\] with a 12 Gy tumor boost to the pre-treatment volume. III. To prospectively collect blood, cerebrospinal fluid, and tumor tissue at diagnosis and second-look surgery (if feasible) for future biology studies. IV. To prospectively measure the incidence of cerebral vascular events (stroke or transient ischemic attacks) in the follow-up period and longitudinally evaluate and model the cognitive, social and behavioral functioning of children and young adults with CNS germinoma through the COG Standardized assessment battery, and compare these outcomes based on tumor characteristics, treatment regimen, and treatment modality. OUTLINE: INDUCTION PHASE: All patients receive carboplatin intravenously (IV) over 15-60 minutes on day 1 and etoposide IV over 90-120 minutes on days 1-3 of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients are then assigned to 1 of 7 strata. STRATUM I: Patients with localized germinoma achieving CR with normalization of markers undergo 3-dimensional conformal radiation therapy (3D-CRT)/3-dimensional conformal proton radiation therapy (3D-CPRT) or intensity-modulated radiation therapy (IMRT)/intensity modulated proton therapy (IMPT) once daily (QD) 5 days a week for 16 days. Patients achieving PR with normalization of markers may undergo second-look surgery. Patients found to have mature teratoma or non-viable tumor undergo 3D-CRT/3D-CPRT or IMRT/IMPT QD 5 days a week for 16 days. Patients with normalization of markers who fail to achieve CR or PR may undergo second-look surgery. Patients found to have mature teratoma or non-viable tumor undergo 3D-CRT/3D-CPRT or IMRT/IMPT QD 5 days a week for 16 days. Patients with bifocal germinoma undergo 3D-CRT/3D-CPRT or IMRT/IMPT QD 5 days a week for 16 days. STRATUM II: Patients with localized germinoma achieving PR with normalization of markers who do not undergo second-look surgery undergo 3D-CRT/3D-CPRT or IMRT/IMPT QD 5 days a week for 20 days. STRATUM III: Patients with localized germinoma with normalization of markers who fail to achieve CR or PR who do not undergo second-look surgery undergo 3D-CRT/3D-CPRT or IMRT/IMPT QD 5 days a week for 24 days. STRATUM IV: Patients with metastatic germinoma achieving CR undergo 3D-CRT/3D-CPRT or IMRT/IMPT QD 5 days a week for 20 days. Patients with metastatic germinoma and normalization of markers who fail to achieve CR may undergo second-look surgery. Patients found to have mature teratoma or non-viable tumor undergo 3D-CRT/3D-CPRT or IMRT/IMPT QD 5 days a week for 20 days. STRATUM V: Patients with metastatic germinoma with normalization of markers who fail to achieve CR who do not undergo second-look surgery undergo 3D-CRT/3D-CPRT or IMRT/IMPT QD 5 days a week for 24 days. STRATUM VI: Patients with basal ganglia and thalamic germinoma achieving CR undergo 3D-CRT/3D-CPRT or IMRT/IMPT QD 5 days a week for 20 days. Patients with basal ganglia and thalamic germinoma and normalization of markers who fail to achieve CR may undergo second-look surgery. Patients found to have mature teratoma or non-viable tumor undergo 3D-CRT/3D-CPRT or IMRT/IMPT QD 5 days a week for 20 days. STRATUM VII: Patients with basal ganglia and thalamic germinoma with normalization of markers who fail to achieve CR who do not undergo second-look surgery undergo 3D-CRT/3D-CPRT or IMRT/IMPT QD 5 days a week for 24 days. Patients with non-normalized tumor markers or PD and no second-look surgery or viable tumor during second-look surgery discontinue protocol therapy. All patients undergo magnetic resonance imaging (MRI) and optional blood and tissue sample collection throughout the study. Patients may undergo lumbar puncture (LP) for CSF sample collection during screening and follow up. After completion of study treatment, patients are followed up every 3 months for 12 months, every 4 months for 24 months, and then annually for up to 120 months.
Arms & interventions
- Radiation3-Dimensional Conformal Proton Radiation Therapy
Undergo 3D-CPRT
- Radiation3-Dimensional Conformal Radiation Therapy
Undergo 3D-CRT
- ProcedureBiospecimen Collection
Undergo blood and CSF sample collection
- DrugCarboplatin
Given IV
- DrugEtoposide
Given IV
- ProcedureIntensity-Modulated Proton Therapy
Undergo IMPT
- RadiationIntensity-Modulated Radiation Therapy
Undergo IMRT
- ProcedureLumbar Puncture
Undergo LP
- ProcedureMagnetic Resonance Imaging
Undergo MRI
- OtherQuestionnaire Administration
Ancillary studies
- ProcedureSurgical Procedure
Undergo second-look surgery
Outcome measures
Primary
Event-free survival (EFS) (Stratum I)
Will be estimated for eligible and evaluable patients assigned to Stratum 1 using Kaplan-Meier (KM) EFS estimates at 2 and 3 years with respective 80% two-sided confidence intervals. Time from initiation of radiation to the first occurrence of any of the following events: biochemical or radiographic disease progression, disease recurrence, second malignant neoplasm, or death from any cause.
Time frame: Evaluated at 2- and 3-years post-radiation initiation
Secondary
EFS (Stratum II)
Time frame: Evaluated at 2- and 3-years post-radiation initiation
EFS (Stratum III)
Time frame: Evaluated at 2- and 3-years post-radiation initiation
Radiographic response rate
Time frame: Following the completion of Induction therapy, approximately 12 weeks post-chemotherapy initiation
Marker tumor response rate
Time frame: Following the completion of Induction therapy, approximately 12 weeks post-chemotherapy initiation
Overall survival (OS)
Time frame: Time from initiation of radiation therapy until death by any cause, up to 10 years post-enrollment
Neuroendocrine dysfunction (including growth hormone deficiency)
Time frame: Time from initiation of radiation treatment until date of diagnosis of neuroendocrine dysfunction event, up to 10 years post-enrollment
Processing speed
Time frame: At 9 months (+/- 3 months), 30 months (+/- 3 months), and 60 months (+/- 3 months) after diagnosis
Eligibility criteria
Study locations (92)
USA Health Strada Patient Care Center
Mobile, Alabama, 36604
Phoenix Childrens Hospital
Phoenix, Arizona, 85016
Arkansas Children's Hospital
Little Rock, Arkansas, 72202-3591
Loma Linda University Medical Center
Loma Linda, California, 92354
Children's Hospital Los Angeles
Los Angeles, California, 90027
UCSF Benioff Children's Hospital Oakland
Oakland, California, 94609
Children's Hospital of Orange County
Orange, California, 92868
Lucile Packard Children's Hospital Stanford University
Palo Alto, California, 94304
Rady Children's Hospital - San Diego
San Diego, California, 92123
UCSF Medical Center-Mission Bay
San Francisco, California, 94158
Children's Hospital Colorado
Aurora, Colorado, 80045
Connecticut Children's Medical Center
Hartford, Connecticut, 06106
Alfred I duPont Hospital for Children
Wilmington, Delaware, 19803
Children's National Medical Center
Washington D.C., District of Columbia, 20010
Memorial Regional Hospital/Joe DiMaggio Children's Hospital
Hollywood, Florida, 33021
Nemours Children's Clinic-Jacksonville
Jacksonville, Florida, 32207
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, 33136
Nicklaus Children's Hospital
Miami, Florida, 33155
Arnold Palmer Hospital for Children
Orlando, Florida, 32806
Nemours Children's Hospital
Orlando, Florida, 32827
Nemours Children's Clinic - Pensacola
Pensacola, Florida, 32504
Sacred Heart Hospital
Pensacola, Florida, 32504
Johns Hopkins All Children's Hospital
St. Petersburg, Florida, 33701
Saint Joseph's Hospital/Children's Hospital-Tampa
Tampa, Florida, 33607
Children's Healthcare of Atlanta - Arthur M Blank Hospital
Atlanta, Georgia, 30329
Kapiolani Medical Center for Women and Children
Honolulu, Hawaii, 96826
Saint Luke's Cancer Institute - Boise
Boise, Idaho, 83712
Lurie Children's Hospital-Chicago
Chicago, Illinois, 60611
University of Illinois
Chicago, Illinois, 60612
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, 60637
Loyola University Medical Center
Maywood, Illinois, 60153
Riley Hospital for Children
Indianapolis, Indiana, 46202
University of Iowa/Holden Comprehensive Cancer Center
Iowa City, Iowa, 52242
Norton Children's Hospital
Louisville, Kentucky, 40202
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, 21287
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
C S Mott Children's Hospital
Ann Arbor, Michigan, 48109
Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital
Grand Rapids, Michigan, 49503
Children's Hospitals and Clinics of Minnesota - Minneapolis
Minneapolis, Minnesota, 55404
University of Minnesota/Masonic Cancer Center
Minneapolis, Minnesota, 55455
Mayo Clinic in Rochester
Rochester, Minnesota, 55905
University of Mississippi Medical Center
Jackson, Mississippi, 39216
Children's Mercy Hospitals and Clinics
Kansas City, Missouri, 64108
Cardinal Glennon Children's Medical Center
St Louis, Missouri, 63104
Washington University School of Medicine
St Louis, Missouri, 63110
Children's Hospital and Medical Center of Omaha
Omaha, Nebraska, 68114
University of Nebraska Medical Center
Omaha, Nebraska, 68198
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
Las Vegas, Nevada, 89135
Summerlin Hospital Medical Center
Las Vegas, Nevada, 89144
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
Lebanon, New Hampshire, 03756
Hackensack University Medical Center
Hackensack, New Jersey, 07601
Saint Peter's University Hospital
New Brunswick, New Jersey, 08901
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
New Brunswick, New Jersey, 08903
Newark Beth Israel Medical Center
Newark, New Jersey, 07112
Saint Joseph's Regional Medical Center
Paterson, New Jersey, 07503
Albany Medical Center
Albany, New York, 12208
The Steven and Alexandra Cohen Children's Medical Center of New York
New Hyde Park, New York, 11040
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, 10016
Mount Sinai Hospital
New York, New York, 10029
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York, New York, 10032
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
State University of New York Upstate Medical University
Syracuse, New York, 13210
Montefiore Medical Center - Moses Campus
The Bronx, New York, 10467
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, 27599
Wake Forest University Health Sciences
Winston-Salem, North Carolina, 27157
Sanford Broadway Medical Center
Fargo, North Dakota, 58122
Rainbow Babies and Childrens Hospital
Cleveland, Ohio, 44106
Nationwide Children's Hospital
Columbus, Ohio, 43205
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
Oregon Health and Science University
Portland, Oregon, 97239
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104
Saint Christopher's Hospital for Children
Philadelphia, Pennsylvania, 19134
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, 15224
Rhode Island Hospital
Providence, Rhode Island, 02903
Prisma Health Richland Hospital
Columbia, South Carolina, 29203
BI-LO Charities Children's Cancer Center
Greenville, South Carolina, 29605
Sanford USD Medical Center - Sioux Falls
Sioux Falls, South Dakota, 57117-5134
Saint Jude Children's Research Hospital
Memphis, Tennessee, 38105
Dell Children's Medical Center of Central Texas
Austin, Texas, 78723
Driscoll Children's Hospital
Corpus Christi, Texas, 78411
Medical City Dallas Hospital
Dallas, Texas, 75230
UT Southwestern/Simmons Cancer Center-Dallas
Dallas, Texas, 75390
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
Houston, Texas, 77030
M D Anderson Cancer Center
Houston, Texas, 77030
Children's Hospital of San Antonio
San Antonio, Texas, 78207
University of Texas Health Science Center at San Antonio
San Antonio, Texas, 78229
Primary Children's Hospital
Salt Lake City, Utah, 84113
University of Virginia Cancer Center
Charlottesville, Virginia, 22908
Children's Hospital of The King's Daughters
Norfolk, Virginia, 23507
Seattle Children's Hospital
Seattle, Washington, 98105
Providence Sacred Heart Medical Center and Children's Hospital
Spokane, Washington, 99204
University of Wisconsin Carbone Cancer Center - University Hospital
Madison, Wisconsin, 53792