Neoadjuvant Chemotherapy With or Without Second-Look Surgery Followed by Radiation Therapy With or Without Peripheral Stem Cell Transplantation in Treating Patients With Intracranial Germ Cell Tumors

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00047320
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 104
• Locations: 106
• Arm: 1
• Duration (Months): 61
• Patients Per Site: 1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Giving a chemotherapy drug before surgery may shrink the tumor so that it is no longer present by conventional imaging and tumor markers from serum and cerebrospinal fluid. Radiation therapy uses high-energy x-rays to damage tumor cells. Peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. Combining different types of therapy may kill more tumor cells.

PURPOSE: This Phase II trial is studying how well neoadjuvant chemotherapy with or without surgery and with or without high dose chemotherapy and peripheral stem cell transplantation, can increase response rates prior to radiation therapy and increase progression free and overall surviving patients with newly diagnosed intracranial germ cell tumors.

Condition or Disease	Intervention/Treatment	Phase
Brain Tumor; Central Nervous System Tumors; Childhood Germ Cell Tumor	Drug: carboplatin; Drug: etoposide; Drug: ifosfamide; Drug: thiotepa; Procedure: adjuvant therapy; Procedure: conventional surgery; Procedure: neoadjuvant therapy; Procedure: peripheral blood stem cell transplantation; Radiation: radiation therapy	Phase 2

Detailed Description

OBJECTIVES:

• Determine the response rate of patients with non-germinomatous germ cell tumors treated with neoadjuvant chemotherapy.

• Determine the progression-free survival and overall survival of patients treated with neoadjuvant chemotherapy with or without second-look surgery followed by radiotherapy with or without autologous peripheral blood stem cell transplantation (PBSCT).

• Determine whether additional complete responses can be achieved after high-dose thiotepa and etoposide with PBSCT in patients with persistently positive markers, histological evidence of residual malignant elements, or unresectable residual tumors after initial neoadjuvant chemotherapy.

• Determine patterns of recurrence in patients treated with this regimen.

• Correlate tumor marker response with radiographic and clinical measures of response, as well as findings at second-look surgery in patients with radiological evidence of residual disease.

OUTLINE:

• Induction chemotherapy:

• Courses 1, 3, and 5: Patients receive carboplatin IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1-3. Beginning on day 4, patients receive filgrastim (G-CSF) IV or subcutaneously (SC) for 10 days or until blood counts recover. Courses are 3 weeks in duration.

• Courses 2, 4, and 6: Patients receive etoposide IV over 1 hour followed by ifosfamide IV over 1 hour on days 1-5. Beginning on day 6, patients receive G-CSF IV or SC for 10 days or until blood counts recover. Courses are 3 weeks in duration.

Patients undergo re-evaluation. Patients with a complete response (CR) go directly to radiotherapy. Approximately 3 weeks after completion of induction chemotherapy, all patients with less than a CR are encouraged to undergo second-look surgery.

After second-look surgery, patients with a CR or a partial response (PR) go directly to radiotherapy. Patients with less than a PR undergo consolidation chemotherapy with peripheral blood stem cell rescue (PBSC) followed by radiotherapy.

• Consolidation chemotherapy: Patients undergo PBSC collection. Patients receive G-CSF SC until PBSC collection is complete. Patients then receive thiotepa IV over 3 hours followed by etoposide IV over 3 hours on days -5 to -3. PBSCs are reinfused on day 0. Beginning on day 1 and continuing until blood counts recover, patients receive G-CSF SC daily.

• Radiotherapy: All patients receive radiotherapy once daily 5 days a week for 5-6 weeks beginning after recovery from induction chemotherapy or second-look surgery or within 9 weeks after PBSC reinfusion.

Patients are followed every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year, and then annually thereafter.

PROJECTED ACCRUAL: A total of 80-100 patients will be accrued for this study within 36-42 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 104 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study To Assess The Ability Of Neoadjuvant Chemotherapy Plus/Minus Second Look Surgery To Eliminate All Measurable Disease Prior To Radiotherapy For NGGCT
• Study Start Date: Jan 1, 2004
• Actual Primary Completion Date: Feb 1, 2009
• Actual Study Completion Date: Feb 1, 2009

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Radiation Therapy (CR from Induction) Patients will receive 6 cycles of Induction chemotherapy consisting of carboplatin and etoposide (Cycles 1, 3, and 5) alternating with ifosfamide and etoposide (Cycles 2, 4, and 6). The entire length of Induction is 18 weeks unless delay occurs due to myelosuppression or unanticipated toxicity. Each cycle of Induction will begin when ANC > 750/L and platelets > 75,000/L and when off filgrastim (G-CSF) for at least 48 hours. Following the Induction phase (weeks 0-18) those patient in CR will undergo radiation therapy.

Drug: carboplatin; Given IV; Other Names: Paraplatin NSC #241240 ; Drug: etoposide; Given IV; Other Names: VP-16 VePesid Etopophos NSC #141540 ; Drug: ifosfamide; Given IV; Other Names: Isophosphamide Iphosphamide Z4942 Ifex NSC #109724 ; Drug: thiotepa; Given IV; Other Names: Tespa Thiophosphamide Triethylenethiophosphoramide Tspa WR-45312 NSC #6396 ; Procedure: adjuvant therapy; Procedure: conventional surgery; Procedure: neoadjuvant therapy; Procedure: peripheral blood stem cell transplantation; Radiation: radiation therapy; craniospinal irradiation; Other Names: Craniospinal irradiation (CSI) followed by boost radiation to the sites of gross disease at diagnosis.

Outcome Measures

Primary Outcome Measures

1. Response to Induction Chemotherapy [18 weeks]

   A patient who achieves a complete or partial response, defined a reduction of at least 65% in tumor size after induction chemotherapy will be considered to have experienced response.

Secondary Outcome Measures

1. The Probability of Event-free Survival (EFS) [At 3 years from study entry]

   Event-free Survival was defined as time from study entry to death from any cause, disease progression or recurrence, or second malignant neoplasm. Event-free survival was estimated by KM estimate.

2. Progression-free Survival (PFS) [At 3 years from study entry]

   Progression-free Survival was defined as time from study entry to disease progression or recurrence. Deaths that are clearly unrelated to disease progression, and second neoplasms are censored in this analysis. Progression -free survival was estimated by KM estimate.

3. Overall Survival (OS) [At 3 years from study entry]

   Overall Survival was defined as time from study entry to death from any cause. Overall survival was estimated by KM estimate.

4. Number of Patients Experiencing Toxic Death [During chemotherapy (up to 18 weeks)]

   Toxic death, defined as death predominantly attributable to treatment-related causes.

5. Occurrence of Non-hematological Grade 4 Toxicity Occurrence of Nonhematological Grade 4 Toxicity [During chemotherapy(up to 18 weeks)]

   The number of patients who experienced non-hematological grade 4 toxicities anytime during chemotherapy.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 24 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• One of the following diagnoses:

• Histologically confirmed intracranial non-germinomatous germ cell tumor (NGGCT) of 1 of the following types:

• Endodermal sinus tumor (yolk sac tumor)

• Embryonal carcinoma

• Choriocarcinoma

• Immature teratoma and teratoma with malignant transformation

• Mixed germ cell tumor

• Histologically confirmed germinoma with elevation of serum/CSF beta human chorionic gonadotropin (HCG) levels greater than 50 mIU/mL or any serum/CSF alpha-fetoprotein (AFP) levels greater than 10 ng/ml or above institutional norm

• Histologically unconfirmed pineal and/or suprasellar tumors with serum/CSF beta HCG levels greater than 50 mIU/mL or AFP levels greater than 10 ng/ml or above institutional norm

• Patients with normal AFP and beta HCG < 50 mIU/mL without histologic diagnosis of a NGGCT or patients with pure germinoma without elevation of tumor marker are ineligible

• Initial diagnosis within the past 31 days

PATIENT CHARACTERISTICS:

Age

• 3 to 24 at diagnosis

Performance status

• No minimum performance level

Life expectancy

• At least 8 weeks

Hematopoietic

• Absolute neutrophil count at least 1,000/mm^3

• Platelet count at least 100,000/mm^3 (transfusion independent)

• Hemoglobin at least 10.0 g/dL (transfusion allowed)

Hepatic

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)

• ALT no greater than 2.5 times ULN

Renal

• Creatinine no greater than 1.5 times ULN OR

• Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min

Pulmonary

• No assisted ventilation

Other

• Seizure disorders allowed

• No patients in status or coma

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patient must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• Not specified

Endocrine therapy

• Prior corticosteroids allowed

• Concurrent corticosteroids allowed

• Concurrent endocrine replacement therapy allowed (e.g., L-thyroxine, testosterone, estrogen, desmopressin acetate)

• No concurrent growth hormone therapy

Radiotherapy

• Not specified

Surgery

• More than 1 prior surgery allowed

Other

• No other prior therapy for malignancy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham	Birmingham	Alabama	United States	35294
2	Phoenix Children's Hospital	Phoenix	Arizona	United States	85016-7710
3	Arkansas Cancer Research Center at University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
4	Southern California Permanente Medical Group	Downey	California	United States	90242-2814
5	Loma Linda University Cancer Institute at Loma Linda University Medical Center	Loma Linda	California	United States	92354
6	Jonathan Jaques Children's Cancer Center at Miller Children's Hospital	Long Beach	California	United States	90801
7	Childrens Hospital Los Angeles	Los Angeles	California	United States	90027
8	Children's Hospital Central California	Madera	California	United States	93638-8762
9	Children's Hospital and Research Center Oakland	Oakland	California	United States	94609
10	Children's Hospital of Orange County	Orange	California	United States	92868
11	Sutter Cancer Center	Sacramento	California	United States	95816
12	Rady Children's Hospital - San Diego	San Diego	California	United States	92123-4282
13	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94115
14	Stanford Cancer Center	Stanford	California	United States	94305-5824
15	Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center	Farmington	Connecticut	United States	06360-2875
16	Alfred I. duPont Hospital for Children	Wilmington	Delaware	United States	19803
17	Children's National Medical Center	Washington	District of Columbia	United States	20010-2970
18	Lee Cancer Care of Lee Memorial Health System	Fort Myers	Florida	United States	33901
19	University of Florida Shands Cancer Center	Gainesville	Florida	United States	32610-0232
20	Nemours Children's Clinic	Jacksonville	Florida	United States	32207
21	University of Miami Sylvester Comprehensive Cancer Center - Miami	Miami	Florida	United States	33136
22	Miami Children's Hospital	Miami	Florida	United States	33155
23	Florida Hospital Cancer Institute at Florida Hospital Orlando	Orlando	Florida	United States	32803-1273
24	Sacred Heart Cancer Center at Sacred Heart Hospital	Pensacola	Florida	United States	32504
25	All Children's Hospital	Saint Petersburg	Florida	United States	33701
26	St. Joseph's Cancer Institute at St. Joseph's Hospital	Tampa	Florida	United States	33607
27	Kaplan Cancer Center at St. Mary's Medical Center	West Palm Beach	Florida	United States	33407
28	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
29	MBCCOP - Medical College of Georgia Cancer Center	Augusta	Georgia	United States	30912-3730
30	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
31	University of Chicago Cancer Research Center	Chicago	Illinois	United States	60637-1470
32	Advocate Lutheran General Cancer Care Center	Park Ridge	Illinois	United States	60068-1174
33	Simmons Cooper Cancer Institute	Springfield	Illinois	United States	62794-9677
34	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202-5289
35	St. Vincent Indianapolis Hospital	Indianapolis	Indiana	United States	46260
36	Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center	Kansas City	Kansas	United States	66160-7357
37	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21231-2410
38	Floating Hospital for Children at Tufts - New England Medical Center	Boston	Massachusetts	United States	02111
39	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
40	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201-1379
41	Butterworth Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503-2560
42	Van Elslander Cancer Center at St. John Hospital and Medical Center	Grosse Pointe Woods	Michigan	United States	48236
43	Breslin Cancer Center at Ingham Regional Medical Center	Lansing	Michigan	United States	48910
44	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
45	Masonic Cancer Center at University of Minnesota	Minneapolis	Minnesota	United States	55455
46	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
47	University of Mississippi Cancer Clinic	Jackson	Mississippi	United States	39216-4505
48	Children's Mercy Hospital	Kansas City	Missouri	United States	64108
49	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
50	Hackensack University Medical Center Cancer Center	Hackensack	New Jersey	United States	07601
51	Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School	New Brunswick	New Jersey	United States	08903
52	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
53	St. Joseph's Hospital and Medical Center	Paterson	New Jersey	United States	07503
54	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87131-5636
55	Albert Einstein Cancer Center at Albert Einstein College of Medicine	Bronx	New York	United States	10461
56	NYU Cancer Institute at New York University Medical Center	New York	New York	United States	10016
57	Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center	New York	New York	United States	10032
58	SUNY Upstate Medical University Hospital	Syracuse	New York	United States	13210
59	New York Medical College	Valhalla	New York	United States	10595
60	Blumenthal Cancer Center at Carolinas Medical Center	Charlotte	North Carolina	United States	28232-2861
61	Duke Comprehensive Cancer Center	Durham	North Carolina	United States	27710
62	Akron Children's Hospital	Akron	Ohio	United States	44308-1062
63	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229-3039
64	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195
65	Nationwide Children's Hospital	Columbus	Ohio	United States	43205-2696
66	Children's Medical Center - Dayton	Dayton	Ohio	United States	45404-1815
67	Oklahoma University Cancer Institute	Oklahoma City	Oklahoma	United States	73104
68	Oregon Health and Science University Cancer Institute	Portland	Oregon	United States	97239-3098
69	Penn State Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
70	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104-9786
71	St. Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States	19134-1095
72	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
73	Rhode Island Hospital Comprehensive Cancer Center	Providence	Rhode Island	United States	02903
74	Hollings Cancer Center at Medical University of South Carolina	Charleston	South Carolina	United States	29425
75	Sanford Cancer Center at Sanford USD Medical Center	Sioux Falls	South Dakota	United States	57117-5039
76	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
77	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232-6838
78	Dell Children's Medical Center of Central Texas	Austin	Texas	United States	78723
79	Driscoll Children's Hospital	Corpus Christi	Texas	United States	78411
80	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas	United States	75390
81	Cook Children's Medical Center - Fort Worth	Fort Worth	Texas	United States	76104
82	Covenant Children's Hospital	Lubbock	Texas	United States	79410
83	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78207
84	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229-3993
85	Primary Children's Medical Center	Salt Lake City	Utah	United States	84113-1100
86	Children's Hospital of The King's Daughters	Norfolk	Virginia	United States	23507-1971
87	West Virginia University Health Sciences Center - Charleston	Charleston	West Virginia	United States	25302
88	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin	United States	54307-3508
89	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin	United States	54449
90	Midwest Children's Cancer Center	Milwaukee	Wisconsin	United States	53226
91	Royal Children's Hospital	Brisbane	Queensland	Australia	4029
92	Royal Children's Hospital	Parkville	Victoria	Australia	3052
93	Princess Margaret Hospital for Children	Perth	Western Australia	Australia	6001
94	Children's & Women's Hospital of British Columbia	Vancouver	British Columbia	Canada	V6H 3V4
95	Janeway Children's Health and Rehabilitation Centre	St. John's	Newfoundland and Labrador	Canada	A1B 3V6
96	IWK Health Centre	Halifax	Nova Scotia	Canada	B3K 6R8
97	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8N 3Z5
98	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
99	Montreal Children's Hospital at McGill University Health Center	Montreal	Quebec	Canada	H3H 1P3
100	Hopital Sainte Justine	Montreal	Quebec	Canada	H3T 1C5
101	Saskatoon Cancer Centre at the University of Saskatchewan	Saskatoon	Saskatchewan	Canada	S7N 4H4
102	Centre Hospitalier Universitaire de Quebec	Quebec		Canada	G1V 4G2
103	Starship Children's Health	Auckland		New Zealand	1
104	Christchurch Hospital	Christchurch		New Zealand
105	Swiss Pediatric Oncology Group Bern	Bern		Switzerland	3010
106	Swiss Pediatric Oncology Group Geneva	Geneva		Switzerland	1205

Sponsors and Collaborators

• Children's Oncology Group
• National Cancer Institute (NCI)

Investigators

• Study Chair: Stewart Goldman, MD, Ann & Robert H Lurie Children's Hospital of Chicago

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT00047320
• Other Study ID Numbers: ACNS0122; CDR0000257664; COG-ACNS0122
• First Posted: Jan 27, 2003
• Last Update Posted: Feb 14, 2018
• Last Verified: Jan 1, 2018

• Keywords provided by Children's Oncology Group: childhood central nervous system germ cell tumor; childhood teratoma; recurrent childhood malignant germ cell tumor; childhood central nervous system choriocarcinoma; childhood central nervous system embryonal tumor; childhood central nervous system germinoma; childhood central nervous system mixed germ cell tumor; childhood central nervous system teratoma; childhood central nervous system yolk sac tumor; recurrent childhood central nervous system embryonal tumor
• Additional relevant MeSH terms: Neoplasms; Neoplasms, Germ Cell and Embryonal; Nervous System Neoplasms; Central Nervous System Neoplasms; Carboplatin; Etoposide; Ifosfamide; Isophosphamide mustard; Thiotepa

Study Results

Participant Flow

Arm/Group Title	Radiation Therapy (CR From Induction)
Arm/Group Description	Patients will receive 6 cycles of Induction chemotherapy consisting of carboplatin and etoposide (Cycles 1, 3, and 5) alternating with ifosfamide and etoposide (Cycles 2, 4, and 6). The entire length of Induction is 18 weeks unless delay occurs due to myelosuppression or unanticipated toxicity. Each cycle of Induction will begin when ANC > 750/L and platelets > 75,000/L and when off filgrastim (G-CSF) for at least 48 hours. Following the Induction phase (weeks 0-18) those patient in CR will undergo radiation therapy. carboplatin: Given IV etoposide: Given IV ifosfamide: Given IV radiation therapy: craniospinal irradiation
Period Title: Overall Study
STARTED	104
COMPLETED	76
NOT COMPLETED	28

Baseline Characteristics

Arm/Group Title	Radiation Therapy (CR From Induction)
Arm/Group Description	Patients will receive 6 cycles of Induction chemotherapy consisting of carboplatin and etoposide (Cycles 1, 3, and 5) alternating with ifosfamide and etoposide (Cycles 2, 4, and 6). The entire length of Induction is 18 weeks unless delay occurs due to myelosuppression or unanticipated toxicity. Each cycle of Induction will begin when ANC > 750/L and platelets > 75,000/L and when off filgrastim (G-CSF) for at least 48 hours. Following the Induction phase (weeks 0-18) those patient in CR will undergo radiation therapy. carboplatin: Given IV etoposide: Given IV ifosfamide: Given IV radiation therapy: craniospinal irradiation
Overall Participants	104
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	12
Sex: Female, Male (Count of Participants)
Female	25 24%
Male	79 76%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1%
Asian	8 7.7%
Native Hawaiian or Other Pacific Islander	2 1.9%
Black or African American	9 8.7%
White	72 69.2%
More than one race	0 0%
Unknown or Not Reported	12 11.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	17 16.3%
Not Hispanic or Latino	85 81.7%
Unknown or Not Reported	2 1.9%
Region of Enrollment (participants) [Number]
United States	88 84.6%
Canada	10 9.6%
Australia	5 4.8%
New Zealand	1 1%

Outcome Measures

1. Primary Outcome

Title	Response to Induction Chemotherapy
Description	A patient who achieves a complete or partial response, defined a reduction of at least 65% in tumor size after induction chemotherapy will be considered to have experienced response.
Time Frame	18 weeks

Outcome Measure Data

Analysis Population Description

Of the 102 eligible patients, 85 completed induction chemotherapy with sufficient data to assess response. Central review response assessment is used.

Arm/Group Title	Radiation Therapy (CR From Induction)
Arm/Group Description	Patients will receive 6 cycles of Induction chemotherapy consisting of carboplatin and etoposide (Cycles 1, 3, and 5) alternating with ifosfamide and etoposide (Cycles 2, 4, and 6). The entire length of Induction is 18 weeks unless delay occurs due to myelosuppression or unanticipated toxicity. Each cycle of Induction will begin when ANC > 750/L and platelets > 75,000/L and when off filgrastim (G-CSF) for at least 48 hours. Following the Induction phase (weeks 0-18) those patient in CR will undergo radiation therapy. carboplatin: Given IV etoposide: Given IV ifosfamide: Given IV thiotepa: Given IV adjuvant therapy conventional surgery neoadjuvant therapy peripheral blood stem cell transplantation radiation therapy: craniospinal irradiation
Measure Participants	85
Responder	74 71.2%
Non-Responder	11 10.6%

2. Secondary Outcome

Title	The Probability of Event-free Survival (EFS)
Description	Event-free Survival was defined as time from study entry to death from any cause, disease progression or recurrence, or second malignant neoplasm. Event-free survival was estimated by KM estimate.
Time Frame	At 3 years from study entry

Outcome Measure Data

Analysis Population Description

Two ineligible patients were excluded. A total of 102 eligible patients were analyzed.

Arm/Group Title	Radiation Therapy (CR From Induction)
Arm/Group Description	Patients will receive 6 cycles of Induction chemotherapy consisting of carboplatin and etoposide (Cycles 1, 3, and 5) alternating with ifosfamide and etoposide (Cycles 2, 4, and 6). The entire length of Induction is 18 weeks unless delay occurs due to myelosuppression or unanticipated toxicity. Each cycle of Induction will begin when ANC > 750/L and platelets > 75,000/L and when off filgrastim (G-CSF) for at least 48 hours. Following the Induction phase (weeks 0-18) those patient in CR will undergo radiation therapy. carboplatin: Given IV etoposide: Given IV ifosfamide: Given IV thiotepa: Given IV adjuvant therapy conventional surgery neoadjuvant therapy peripheral blood stem cell transplantation radiation therapy: craniospinal irradiation
Measure Participants	102
Number (95% Confidence Interval) [Probability]	0.837

3. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	Progression-free Survival was defined as time from study entry to disease progression or recurrence. Deaths that are clearly unrelated to disease progression, and second neoplasms are censored in this analysis. Progression -free survival was estimated by KM estimate.
Time Frame	At 3 years from study entry

Outcome Measure Data

Analysis Population Description

Two ineligible patients were excluded. A total of 102 eligible patients were analyzed. one patient died without the disease progression reported. But the death was due to the disease. The death was counted as "event" when progression-free survival (PFS) was calculated. So EFS and PFS at 3 years were same.

Arm/Group Title	Radiation Therapy (CR From Induction)
Arm/Group Description	Patients will receive 6 cycles of Induction chemotherapy consisting of carboplatin and etoposide (Cycles 1, 3, and 5) alternating with ifosfamide and etoposide (Cycles 2, 4, and 6). The entire length of Induction is 18 weeks unless delay occurs due to myelosuppression or unanticipated toxicity. Each cycle of Induction will begin when ANC > 750/L and platelets > 75,000/L and when off filgrastim (G-CSF) for at least 48 hours. Following the Induction phase (weeks 0-18) those patient in CR will undergo radiation therapy. carboplatin: Given IV etoposide: Given IV ifosfamide: Given IV thiotepa: Given IV adjuvant therapy conventional surgery neoadjuvant therapy peripheral blood stem cell transplantation radiation therapy: craniospinal irradiation
Measure Participants	102
Number (95% Confidence Interval) [Probability]	0.837

4. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall Survival was defined as time from study entry to death from any cause. Overall survival was estimated by KM estimate.
Time Frame	At 3 years from study entry

Outcome Measure Data

Analysis Population Description

Two ineligible patients were excluded. A total of 102 eligible patients were analyzed.

Arm/Group Title	Radiation Therapy (CR From Induction)
Arm/Group Description	Patients will receive 6 cycles of Induction chemotherapy consisting of carboplatin and etoposide (Cycles 1, 3, and 5) alternating with ifosfamide and etoposide (Cycles 2, 4, and 6). The entire length of Induction is 18 weeks unless delay occurs due to myelosuppression or unanticipated toxicity. Each cycle of Induction will begin when ANC > 750/L and platelets > 75,000/L and when off filgrastim (G-CSF) for at least 48 hours. Following the Induction phase (weeks 0-18) those patient in CR will undergo radiation therapy. carboplatin: Given IV etoposide: Given IV ifosfamide: Given IV thiotepa: Given IV adjuvant therapy conventional surgery neoadjuvant therapy peripheral blood stem cell transplantation radiation therapy: craniospinal irradiation
Measure Participants	102
Number (95% Confidence Interval) [Probability]	0.927

5. Secondary Outcome

Title	Number of Patients Experiencing Toxic Death
Description	Toxic death, defined as death predominantly attributable to treatment-related causes.
Time Frame	During chemotherapy (up to 18 weeks)

Outcome Measure Data

Analysis Population Description

A total of 102 eligible patients treated with induction chemotherapy were included.

Arm/Group Title	Radiation Therapy (CR From Induction)
Arm/Group Description	Patients will receive 6 cycles of Induction chemotherapy consisting of carboplatin and etoposide (Cycles 1, 3, and 5) alternating with ifosfamide and etoposide (Cycles 2, 4, and 6). The entire length of Induction is 18 weeks unless delay occurs due to myelosuppression or unanticipated toxicity. Each cycle of Induction will begin when ANC > 750/L and platelets > 75,000/L and when off filgrastim (G-CSF) for at least 48 hours. Following the Induction phase (weeks 0-18) those patient in CR will undergo radiation therapy. carboplatin: Given IV etoposide: Given IV ifosfamide: Given IV thiotepa: Given IV adjuvant therapy conventional surgery neoadjuvant therapy peripheral blood stem cell transplantation radiation therapy: craniospinal irradiation
Measure Participants	102
Count of Participants [Participants]	0 0%

6. Secondary Outcome

Title	Occurrence of Non-hematological Grade 4 Toxicity Occurrence of Nonhematological Grade 4 Toxicity
Description	The number of patients who experienced non-hematological grade 4 toxicities anytime during chemotherapy.
Time Frame	During chemotherapy(up to 18 weeks)

Outcome Measure Data

Analysis Population Description

A total of 102 eligible patients treated with induction chemotherapy were included.

Arm/Group Title	Radiation Therapy (CR From Induction)
Arm/Group Description	Patients will receive 6 cycles of Induction chemotherapy consisting of carboplatin and etoposide (Cycles 1, 3, and 5) alternating with ifosfamide and etoposide (Cycles 2, 4, and 6). The entire length of Induction is 18 weeks unless delay occurs due to myelosuppression or unanticipated toxicity. Each cycle of Induction will begin when ANC > 750/L and platelets > 75,000/L and when off filgrastim (G-CSF) for at least 48 hours. Following the Induction phase (weeks 0-18) those patient in CR will undergo radiation therapy. carboplatin: Given IV etoposide: Given IV ifosfamide: Given IV thiotepa: Given IV adjuvant therapy conventional surgery neoadjuvant therapy peripheral blood stem cell transplantation radiation therapy: craniospinal irradiation
Measure Participants	102
Number (95% Confidence Interval) [participants]	22 21.2%

Adverse Events

Adverse Event Reporting Description	104 patients enrolled, 2 are ineligible and not included in adverse event reporting. Therefore, adverse events participants reported is 102.
Arm/Group Title	Radiation Therapy (CR From Induction)
Arm/Group Description	Patients will receive 6 cycles of Induction chemotherapy consisting of carboplatin and etoposide (Cycles 1, 3, and 5) alternating with ifosfamide and etoposide (Cycles 2, 4, and 6). The entire length of Induction is 18 weeks unless delay occurs due to myelosuppression or unanticipated toxicity. Each cycle of Induction will begin when ANC > 750/L and platelets > 75,000/L and when off filgrastim (G-CSF) for at least 48 hours. Following the Induction phase (weeks 0-18) those patient in CR will undergo radiation therapy. carboplatin: Given IV etoposide: Given IV ifosfamide: Given IV radiation therapy: craniospinal irradiation
All Cause Mortality
	Radiation Therapy (CR From Induction)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Radiation Therapy (CR From Induction)
	Affected / at Risk (%)	# Events
Total	8/102 (7.8%)
Blood and lymphatic system disorders
Febrile neutropenia	1/102 (1%)	1
Gastrointestinal disorders
Nausea	1/102 (1%)	1
Investigations
Lymphocyte count decreased	1/102 (1%)	2
Neutrophil count decreased	3/102 (2.9%)	5
Platelet count decreased	1/102 (1%)	1
White blood cell decreased	1/102 (1%)	2
Metabolism and nutrition disorders
Hyperkalemia	1/102 (1%)	1
Hypernatremia	1/102 (1%)	3
Hypokalemia	2/102 (2%)	3
Hypophosphatemia	1/102 (1%)	1
Nervous system disorders
Headache	1/102 (1%)	1
Seizure	1/102 (1%)	1
Other (Not Including Serious) Adverse Events
	Radiation Therapy (CR From Induction)
	Affected / at Risk (%)	# Events
Total	70/102 (68.6%)
Blood and lymphatic system disorders
Anemia	51/102 (50%)	108
Febrile neutropenia	8/102 (7.8%)	9
Gastrointestinal disorders
Nausea	8/102 (7.8%)	16
Vomiting	15/102 (14.7%)	28
Infections and infestations
Infections and infestations - Other, specify	8/102 (7.8%)	10
Investigations
Alanine aminotransferase increased	23/102 (22.5%)	39
Aspartate aminotransferase increased	15/102 (14.7%)	22
Lymphocyte count decreased	19/102 (18.6%)	42
Neutrophil count decreased	53/102 (52%)	104
Platelet count decreased	53/102 (52%)	96
White blood cell decreased	48/102 (47.1%)	114
Metabolism and nutrition disorders
Hyperglycemia	18/102 (17.6%)	37
Hyperkalemia	8/102 (7.8%)	8
Hypermagnesemia	10/102 (9.8%)	11
Hypernatremia	20/102 (19.6%)	32
Hypoalbuminemia	6/102 (5.9%)	7
Hypocalcemia	15/102 (14.7%)	22
Hypokalemia	26/102 (25.5%)	39
Hypomagnesemia	9/102 (8.8%)	13
Hyponatremia	31/102 (30.4%)	57
Hypophosphatemia	8/102 (7.8%)	12
Nervous system disorders
Headache	8/102 (7.8%)	8

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Must obtain prior Sponsor approval.