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Radiotherapy Alone VS. Chemotherapy Followed By Response-Based Radiotherapy For Newly Diagnosed Primary CNS Germinoma


Phase 3
3 Years
25 Years
Not Enrolling
Both
Brain Tumor, Central Nervous System Tumor

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Trial Information

Radiotherapy Alone VS. Chemotherapy Followed By Response-Based Radiotherapy For Newly Diagnosed Primary CNS Germinoma


OBJECTIVES:

Primary

- Compare event-free survival and overall survival of patients with newly diagnosed
primary CNS germ cell tumor treated with conventional radiotherapy alone (regimen A) vs
chemotherapy followed by tumor response-based radiotherapy (regimen B).

Secondary

- Determine the complete response rate in patients treated with regimen B.

- Determine the acute and subacute toxicity of regimen B in these patients.

- Compare treatment-related morbidity, in terms of verbal learning and memory, executive
functioning, and quality of life, in patients treated with these regimens.

- Determine the prognostic value of baseline serum, lumbar, and intraventricular levels
of human chorionic gonadotropin levels from patients treated with these regimens.

- Determine the prognostic value of extent of disease (M+ vs modified M+ vs M0) on
event-free survival and overall survival of patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to tumor
location (pineal vs suprasellar vs pineal + suprasellar or other), and disease stage
(disseminated vs occult multi-focal vs localized). Patients are randomized to 1 of 2
treatment regimens.

All patients undergo an operative procedure (endoscopic biopsy, stereotactic biopsy, or open
craniotomy) to confirm the diagnosis of pure germ cell germinoma followed by an
intraoperative and perioperative staging evaluation.

- Regimen A (radiotherapy only): Within 52 days of surgery, patients undergo
standard-dose radiotherapy once daily on days 1-5 for approximately 5-6 weeks.

- Regimen B (chemotherapy plus radiotherapy):

- Courses 1 and 2: Patients receive carboplatin IV over 1 hour on days 1 and 2 and
etoposide IV over 2 hours on days 1-3. Treatment repeats every 21 days for 2
courses.

Patients achieving a complete response (CR) proceed to reduced-dose radiotherapy. Patients
with minimal residual disease (MRD), a partial response (PR), or stable disease (SD) receive
chemotherapy courses 3 and 4 as outlined below. Patients with progressive disease undergo a
second surgical procedure for biopsy and are restaged. Patients with a confirmed diagnosis
of germ cell tumor with no change in tumor markers and no new lesions after restaging
proceed to chemotherapy courses 3 and 4.

- Courses 3 and 4: Patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide
IV over 1 hour on days 2 and 3, and filgrastim (G-CSF) subcutaneously or IV beginning
on day 4 and continuing until blood counts recover. Treatment repeats every 21 days for
2 courses.

Patients achieving a CR or MRD proceed to reduced-dose radiotherapy. Patients with a PR, SD,
or progressive disease are restaged. Patients with a confirmed diagnosis of germ cell tumor
after restaging undergo standard radiotherapy as in regimen A.

- Reduced-dose radiotherapy: Within 6 weeks of starting course 4, patients undergo
lower-dose radiotherapy once daily on days 1-5 for 5 weeks.

Treatment in both regimens continues in the absence of unacceptable toxicity or in the event
that a non-germinomatous germ cell tumor is detected.

Quality of life and neuropsychological function within the domains of intelligence,
attention-concentration, memory, and executive functioning are assessed at 9, 30, and 60
months after diagnosis.

Patients are followed every 4 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 225 patients (approximately 112 per treatment regimen) will be
accrued for this study within 5 years.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically confirmed primary CNS pure germ cell tumor

- Diagnosed within the past 31 days

- Meets any 1 OR none (i.e., M0 [localized disease]) of the following staging criteria:

- M+ (disseminated disease)

- Leptomeningeal or intraventricular metastases visualized on MRI scans of
the brain and spine

- Clumps of tumor cells on lumbar cerebrospinal fluid (CSF) cytology

- Visible tumor studding the walls of the lateral or third ventricles noted
during endoscopy or surgery

- Primary tumor arising within the parenchyma of the brain, brainstem, or
spinal cord

- Measurable multi-focal tumors arising in both the pineal and suprasellar
regions (i.e., multiple midline tumors)

- Infiltrative, intra-axial extension on brain MRI > 1 cm beyond enhancing
tumor

- Modified M+ (occult multi-focal disease)

- M0 at diagnosis with a localized pineal region tumor with signs and
symptoms of diabetes insipidus without measurable disease in the
suprasellar region

- Lumbar CSF assay meeting criteria for the following marker profiles:

- Serum and CSF beta human chorionic gonadotropin (β-HCG) ≤ 50 IU/dL

- Serum alpha fetoprotein (AFP) ≤ 10 IU/L AND ≤ institutional norm

- CSF AFP ≤ 2.0 IU/L AND ≤ institutional norm

PATIENT CHARACTERISTICS:

Age

- 3 to 25

Performance status

- Not specified

Life expectancy

- Not specified

Hematopoietic

- Absolute neutrophil count > 1,000/mm^3

- Platelet count > 100,000/mm^3 (transfusion independent)

- Hemoglobin > 10.0 g/dL (transfusion allowed)

Hepatic

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST or ALT < 2.5 times ULN

Renal

- Creatinine adjusted according to age as follows*:

- No greater than 0.4 mg/dL (≤ 5 months)

- No greater than 0.5 mg/dL (6 months -11 months)

- No greater than 0.6 mg/dL (1 year-23 months)

- No greater than 0.8 mg/dL (2 years-5 years)

- No greater than 1.0 mg/dL (6 years-9 years)

- No greater than 1.2 mg/dL (10 years-12 years)

- No greater than 1.4 mg/dL (13 years and over [female])

- No greater than 1.5 mg/dL (13 years to 15 years [male])

- No greater than 1.7 mg/dL (16 years and over [male]) AND

- Creatinine clearance OR radioisotope glomerular filtration rate > 70 mL/min

Other

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Euthyroid (with or without levothyroxine sodium therapy) as determined by normal T4 ±
thyroid-stimulating hormone levels*

- Diabetes insipidus allowed provided patient is relatively stable on desmopressin
acetate

- Normal endogenous cortisol function*

- Adequate antidiuretic hormone reserves* NOTE: *Unless receiving replacement therapy

PRIOR CONCURRENT THERAPY:

Biologic therapy

- Not specified

Chemotherapy

- Not specified

Endocrine therapy

- Concurrent replacement hormones allowed (e.g., corticosteroids, levothyroxine sodium,
and desmopressin acetate)

Radiotherapy

- Not specified

Surgery

- Prior surgery for germ cell tumor allowed

Other

- No other prior therapy for germ cell tumor

- Concurrent anticonvulsants allowed

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Event-free survival

Outcome Description:

There is a potential for an early time lag in the discovery of treatment failure events in patients on regimen B. Although it is unlikely that the bias that is introduced will be large enough to noticeably influence the properties of the usual logrank test in this case, a partially-grouped logrank test 34 with grouping time of 6 months will be employed to minimize this bias.

Outcome Time Frame:

Time from study entry to disease progression, disease recurrence or the development of new lesions, the occurrence of the second malignant neoplasm, or death from any cause, assessed up to 5 years

Safety Issue:

No

Principal Investigator

Jeffrey C. Allen, MD

Investigator Role:

Study Chair

Investigator Affiliation:

New York University School of Medicine

Authority:

United States: Federal Government

Study ID:

ACNS0232

NCT ID:

NCT00085098

Start Date:

January 2007

Completion Date:

Related Keywords:

  • Brain Tumor
  • Central Nervous System Tumor
  • childhood central nervous system germ cell tumor
  • Brain Neoplasms
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms
  • Neoplasms, Germ Cell and Embryonal

Name

Location

Roswell Park Cancer InstituteBuffalo, New York  14263
Memorial Sloan-Kettering Cancer CenterNew York, New York  10021
Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
Mayo Clinic Cancer CenterRochester, Minnesota  55905
Walter Reed Army Medical CenterWashington, District of Columbia  20307-5000
University of Chicago Cancer Research CenterChicago, Illinois  60637
Barbara Ann Karmanos Cancer InstituteDetroit, Michigan  48201
University of Texas Health Science Center at San AntonioSan Antonio, Texas  78284-7811
CCOP - KalamazooKalamazoo, Michigan  49007-3731
Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health CenterFarmington, Connecticut  06360-2875
Penn State Cancer Institute at Milton S. Hershey Medical CenterHershey, Pennsylvania  17033-0850
Sanford Cancer Center at Sanford USD Medical CenterSioux Falls, South Dakota  57117-5039
Marshfield Clinic - Marshfield CenterMarshfield, Wisconsin  54449
Newark Beth Israel Medical CenterNewark, New Jersey  07112
Ellis Fischel Cancer Center at University of Missouri - ColumbiaColumbia, Missouri  65203
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel HillChapel Hill, North Carolina  27599-7570
Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, Maryland  21231-2410
Cleveland Clinic Taussig Cancer CenterCleveland, Ohio  44195
Sutter Cancer CenterSacramento, California  95816
Children's National Medical CenterWashington, District of Columbia  20010-2970
Children's Mercy HospitalKansas City, Missouri  64108
St. Joseph's Hospital and Medical CenterPaterson, New Jersey  07503
Children's Hospital of PittsburghPittsburgh, Pennsylvania  15213
Children's Hospital and Regional Medical Center - SeattleSeattle, Washington  98105
Nemours Children's ClinicJacksonville, Florida  32207
Miami Children's HospitalMiami, Florida  33155-4069
All Children's HospitalSt. Petersburg, Florida  33701
Children's Memorial Hospital - ChicagoChicago, Illinois  60614
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer InstituteBoston, Massachusetts  02115
Cardinal Glennon Children's HospitalSaint Louis, Missouri  63104
St. Christopher's Hospital for ChildrenPhiladelphia, Pennsylvania  19134-1095
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
Driscoll Children's HospitalCorpus Christi, Texas  78466
Cook Children's Medical Center - Fort WorthFort Worth, Texas  76104
Phoenix Children's HospitalPhoenix, Arizona  85016-7710
Southern California Permanente Medical GroupDowney, California  90242
Children's Hospital Central CaliforniaMadera, California  93638-8762
Kosair Children's HospitalLouisville, Kentucky  40202-3830
Children's Medical Center - DaytonDayton, Ohio  45404
Palmetto Health South Carolina Cancer CenterColumbia, South Carolina  29203
East Tennessee Children's HospitalKnoxville, Tennessee  37901
Midwest Children's Cancer Center at Children's Hospital of WisconsinMilwaukee, Wisconsin  53226
Arkansas Cancer Research Center at University of Arkansas for Medical SciencesLittle Rock, Arkansas  72205
Blumenthal Cancer Center at Carolinas Medical CenterCharlotte, North Carolina  28232-2861
Overlook HospitalSummit, New Jersey  07902-0220
Loma Linda University Cancer Institute at Loma Linda University Medical CenterLoma Linda, California  92354
Jonathan Jaques Children's Cancer Center at Miller Children's HospitalLong Beach, California  90801
Lee Cancer Care of Lee Memorial Health SystemFort Myers, Florida  33901
Florida Hospital Cancer Institute at Florida Hospital OrlandoOrlando, Florida  32803-1273
Sacred Heart Cancer Center at Sacred Heart HospitalPensacola, Florida  32504
St. Joseph's Cancer Institute at St. Joseph's HospitalTampa, Florida  33607
Winship Cancer Institute of Emory UniversityAtlanta, Georgia  30322
Advocate Christ Medical CenterOak Lawn, Illinois  60453
Floating Hospital for Children at Tufts - New England Medical CenterBoston, Massachusetts  02111
Albert Einstein Cancer Center at Albert Einstein College of MedicineBronx, New York  10461
NYU Cancer Institute at New York University Medical CenterNew York, New York  10016
Stony Brook University Cancer CenterStony Brook, New York  11794-8174
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Rainbow Babies and Children's HospitalCleveland, Ohio  44106-5000
Rhode Island Hospital Comprehensive Cancer CenterProvidence, Rhode Island  02903
Hollings Cancer Center at Medical University of South CarolinaCharleston, South Carolina  29425
Texas Tech University Health Sciences Center School of Medicine - AmarilloAmarillo, Texas  79106
Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - DallasDallas, Texas  75390
Baylor University Medical Center - HoustonHouston, Texas  77030-2399
Methodist Children's Hospital of South TexasSan Antonio, Texas  78229-3993
Primary Children's Medical CenterSalt Lake City, Utah  84113-1100
Saint Peter's University HospitalNew Brunswick, New Jersey  08901-1780
James P. Wilmot Cancer Center at University of Rochester Medical CenterRochester, New York  14642
Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical CenterLos Angeles, California  90048-1865
Children's Hospital Center for Cancer and Blood DisordersAurora, Colorado  80045
Alfred I. duPont Hospital for ChildrenWilmington, Delaware  19803
Mountain States Tumor Institute at St. Luke's Regional Medical CenterBoise, Idaho  83712-6297
Lucille P. Markey Cancer Center at University of KentuckyLexington, Kentucky  40536-0093
Tulane Cancer Center Office of Clinical ResearchAlexandria, Louisiana  71315-3198
CancerCare of Maine at Eastern Maine Medical CenterBangor, Maine  04401
C.S. Mott Children's Hospital at University of Michigan Medical CenterAnn Arbor, Michigan  48109-0286
Butterworth Hospital at Spectrum HealthGrand Rapids, Michigan  49503-2560
Children's Hospitals and Clinics of Minnesota - MinneapolisMinneapolis, Minnesota  55404
University of Mississippi Cancer ClinicJackson, Mississippi  39216-4505
Siteman Cancer Center at Barnes-Jewish Hospital - Saint LouisSt. Louis, Missouri  63110
CCOP - Nevada Cancer Research FoundationLas Vegas, Nevada  89109-2306
Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical SchoolNew Brunswick, New Jersey  08903
University of New Mexico Cancer CenterAlbuquerque, New Mexico  87131-5636
Maimonides Cancer Center at Maimonides Medical CenterBrooklyn, New York  11219
Herbert Irving Comprehensive Cancer Center at Columbia University Medical CenterNew York, New York  10032
Akron Children's HospitalAkron, Ohio  44308-1062
Oklahoma University Cancer InstituteOklahoma City, Oklahoma  73104
Legacy Emanuel Hospital and Health Center and Children's HospitalPortland, Oregon  97227
Dell Children's Medical Center of Central TexasAustin, Texas  78723
M. D. Anderson Cancer Center at University of TexasHouston, Texas  77030-4009
West Virginia University Health Sciences Center - CharlestonCharleston, West Virginia  25302
Stanford Cancer CenterStanford, California  94305-5824
University of Miami Sylvester Comprehensive Cancer Center - MiamiMiami, Florida  33136
Lurleen Wallace Comprehensive Cancer at University of Alabama - BirminghamBirmingham, Alabama  35294
Greenville Hospital Cancer CenterGreenville, South Carolina  29605