Etoposide Plus Radiation Therapy Followed by Combination Chemotherapy in Treating Children With Newly Diagnosed Advanced Medulloblastoma

A Phase I/II Feasibility Study of Oral Etoposide Given Concurrently With Radiotherapy Followed With Dose Intensive Adjuvant Chemotherapy for Children With Newly Diagnosed High Stage Medulloblastoma

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining radiation therapy with chemotherapy may kill more tumor cells.

PURPOSE: Phase II trial to study the effectiveness of etoposide plus radiation therapy followed by combination chemotherapy in treating children with newly diagnosed advanced medulloblastoma.

Study Overview

• Status: Completed
• Conditions: Brain Tumors; Central Nervous System Tumors
• Intervention / Treatment: Drug: cyclophosphamide; Radiation: radiation therapy; Drug: etoposide; Drug: vincristine sulfate; Drug: cisplatin; Biological: filgrastim

Detailed Description

OBJECTIVES:

• Assess the response rate and toxicity of oral etoposide and radiotherapy in children with newly diagnosed high stage medulloblastoma.
• Compare the response rate and toxicity of these patients to historical control patients registered on POG #9031.
• Estimate the 2-year event-free survival and overall survival of these patients.
• Evaluate the toxicity of dose intensive chemotherapy with oral etoposide, cisplatin, cyclophosphamide, and vincristine following craniospinal irradiation in these patients.

OUTLINE: Patients begin treatment within 1 month of surgery. Patients receive 6 weeks of radiotherapy to the head and spine, with boosts to the posterior fossa and to sites of metastasis. Patients also receive 2 courses of oral etoposide once daily for 3 weeks concurrent with and immediately following radiotherapy (weeks 1-3 and 5-7).

Patients then receive adjuvant chemotherapy consisting of cisplatin IV once every 4 weeks for 3 courses beginning on week 11, oral etoposide daily for 21 days every 4 weeks for 3 courses (weeks 11, 15, and 19), cyclophosphamide IV on days 1 and 2 with filgrastim (G-CSF) SQ daily for at least 10 days every 4 weeks for 8 courses (weeks 23-51), and vincristine IV on days 1, 8, and 15 every 4 weeks for 8 courses (weeks 23-51).

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

PROJECTED ACCRUAL: A total of 48 patients will be accrued for this study within about 2 years.

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2T 5C7
      • Alberta Children's Hospital
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • Children's Hospital
    • Ottawa, Ontario, Canada, K1H 8L1
      • Children's Hospital of Eastern Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Hopital Sainte Justine
    • Montreal, Quebec, Canada, H3H 1P3
      • McGill University Health Center - Montreal Children's Hospital
    • Sainte Foy, Quebec, Canada, GIV 4G2
      • Centre Hospitalier de l'Universite Laval
• Netherlands
  • Groningen, Netherlands, 9713 EZ
    • Academisch Ziekenhuis Groningen
• Puerto Rico
  • Santurce, Puerto Rico, 00912
    • San Jorge Childrens Hospital
• Switzerland
  • Bern, Switzerland, CH 3010
    • Swiss Pediatric Oncology Group Bern
  • Geneva, Switzerland, 1211
    • Clinique de Pediatrie
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-3300
      • University of Alabama at Birmingham Comprehensive Cancer Center
    • Mobile, Alabama, United States, 36688
      • MBCCOP - Gulf Coast
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Arizona Cancer Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • La Jolla, California, United States, 92093-0658
      • University of California San Diego Cancer Center
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital at Stanford
    • Sacramento, California, United States, 95816
      • Sutter Cancer Center
    • Sacramento, California, United States, 95817
      • University of California Davis Medical Center
    • San Diego, California, United States, 92120
      • Kaiser Permanente-Southern California Permanente Medical Group
    • San Diego, California, United States, 92134-3202
      • Naval Medical Center - San Diego
    • San Diego, California, United States, 92123-4282
      • Children's Hospital and Health Center
    • Santa Clara, California, United States, 95051-5386
      • Kaiser Permanente Medical Center - Santa Clara
  • Connecticut
    • New Haven, Connecticut, United States, 06520-8028
      • Yale Comprehensive Cancer Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20307-5000
      • Walter Reed Army Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610-100277
      • Shands Hospital and Clinics, University of Florida
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic
    • Miami, Florida, United States, 33136
      • Sylvester Cancer Center, University of Miami
    • Miami, Florida, United States, 33155
      • Miami Children's Hospital
    • Orlando, Florida, United States, 32803
      • Walt Disney Memorial Cancer Institute
    • Tampa, Florida, United States, 33682-7757
      • CCOP - Florida Pediatric
    • West Palm Beach, Florida, United States, 33407
      • St. Mary's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital - Atlanta
  • Hawaii
    • Honolulu, Hawaii, United States, 96859-5000
      • Tripler Army Medical Center
    • Honolulu, Hawaii, United States, 96813
      • Cancer Research Center of Hawaii
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush-Presbyterian-St. Luke's Medical Center
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital, Chicago
    • Oak Lawn, Illinois, United States, 60453
      • Hope Children's Hospital
    • Peoria, Illinois, United States, 61637
      • Saint Jude Midwest Affiliate
  • Kansas
    • Kansas City, Kansas, United States, 66160-7357
      • University of Kansas Medical Center
    • Wichita, Kansas, United States, 67214-3882
      • CCOP - Wichita
    • Wichita, Kansas, United States, 67214
      • Via Christi Regional Medical Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University School of Medicine
    • New Orleans, Louisiana, United States, 70121
      • CCOP - Ochsner
    • New Orleans, Louisiana, United States, 70112
      • MBCCOP - LSU Health Sciences Center
  • Maine
    • Bangor, Maine, United States, 04401
      • Eastern Maine Medical Center
    • Portland, Maine, United States, 04101
      • Maine Children's Cancer Program
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Marlene & Stewart Greenebaum Cancer Center, University of Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Johns Hopkins Oncology Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
    • Boston, Massachusetts, United States, 02111
      • Boston Floating Hospital Infants and Children
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Memorial Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Children's Hospital of Michigan
    • Detroit, Michigan, United States, 48236
      • St. John's Hospital and Medical Center
    • Flint, Michigan, United States, 48503
      • Hurley Medical Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216-4505
      • University of Mississippi Medical Center
    • Keesler AFB, Mississippi, United States, 39534-2576
      • Keesler Medical Center - Keesler AFB
  • Missouri
    • Columbia, Missouri, United States, 65212
      • University of Missouri-Columbia Hospital and Clinics
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • Saint Louis, Missouri, United States, 63104
      • Cardinal Glennon Children's Hospital
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756-0002
      • Norris Cotton Cancer Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
    • Hackensack, New Jersey, United States, 07601
      • CCOP - Northern New Jersey
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico School of Medicine
  • New York
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute
    • New Hyde Park, New York, United States, 11042
      • Schneider Children's Hospital
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
    • Rochester, New York, United States, 14642
      • University of Rochester Cancer Center
    • Stony Brook, New York, United States, 11790-7775
      • State University of New York Health Sciences Center - Stony Brook
    • Syracuse, New York, United States, 13210
      • State University of New York - Upstate Medical University
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Mission Saint Joseph's Health System
    • Charlotte, North Carolina, United States, 28232-2861
      • Carolinas Medical Center
    • Charlotte, North Carolina, United States, 28233-3549
      • Presbyterian Healthcare
    • Durham, North Carolina, United States, 27710
      • Duke Comprehensive Cancer Center
    • Greenville, North Carolina, United States, 27858-4354
      • East Carolina University School of Medicine
    • Winston-Salem, North Carolina, United States, 27157-1082
      • Comprehensive Cancer Center at Wake Forest University
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73126-0307
      • Oklahoma Memorial Hospital
    • Tulsa, Oklahoma, United States, 74136
      • Natalie Warren Bryant Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97213
      • CCOP - Columbia River Program
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Hospital and Health Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19134-1095
      • St. Christopher's Hospital for Children
  • South Carolina
    • Charleston, South Carolina, United States, 29425-0721
      • Medical University of South Carolina
    • Greenville, South Carolina, United States, 29605
      • Children's Hospital of Greenville Hospital System
  • Tennessee
    • Johnson City, Tennessee, United States, 37614-0622
      • James H. Quillen College of Medicine
    • Memphis, Tennessee, United States, 38105-2794
      • Saint Jude Children's Research Hospital
  • Texas
    • Dallas, Texas, United States, 75230
      • Medical City Dallas Hospital
    • Dallas, Texas, United States, 75235-9154
      • Simmons Cancer Center - Dallas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center - Fort Worth
    • Galveston, Texas, United States, 77555-0209
      • University of Texas Medical Branch
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Lackland Air Force Base, Texas, United States, 78236-5300
      • San Antonio Military Pediatric Cancer and Blood Disorders Center
    • San Antonio, Texas, United States, 78284-7811
      • University of Texas Health Science Center at San Antonio
    • San Antonio, Texas, United States, 78229-3900
      • MBCCOP - South Texas Pediatric
    • Temple, Texas, United States, 76508
      • Scott and White Clinic
  • Vermont
    • Burlington, Vermont, United States, 05401-3498
      • Vermont Cancer Center
  • Virginia
    • Falls Church, Virginia, United States, 22046
      • Inova Fairfax Hospital
    • Portsmouth, Virginia, United States, 23708-2197
      • Naval Medical Center, Portsmouth
    • Richmond, Virginia, United States, 23298-0037
      • Massey Cancer Center
    • Roanoke, Virginia, United States, 24029
      • Carilion Roanoke Community Hospital
  • Washington
    • Tacoma, Washington, United States, 98431-5000
      • Madigan Army Medical Center
  • West Virginia
    • Charleston, West Virginia, United States, 25304
      • West Virginia University Medical School-Charleston
    • Morgantown, West Virginia, United States, 26506-9162
      • West Virginia University Hospitals
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54307-3508
      • St. Vincent Hospital
    • Milwaukee, Wisconsin, United States, 53226
      • Midwest Children's Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically diagnosed advanced (high grade) childhood medulloblastoma
• Residual disease of at least 1.5 cm2 in size on MRI or CT scan OR
• Evidence of CNS or extraneural metastases

PATIENT CHARACTERISTICS:

Age:

• 3 to 21

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• SGPT less than 5 times normal
• Bilirubin less than 1.5 mg/dL

Renal:

• Creatinine less than 1.7 mg/dL OR
• Creatinine clearance greater than 70 mL/min

Other:

• Not pregnant or nursing
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• Prior corticosteroids allowed

Radiotherapy:

• No prior radiotherapy

Surgery:

• Not specified

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment 1, Etoposide, 50mg/m2/day; Patients begin treatment within 1 month of surgery. Patients receive 6 weeks of radiation therapy to the head and spine, with boosts to the posterior fossa and to sites of metastasis. Patients also receive 2 courses of oral etoposide once daily for 3 weeks concurrent with and immediately following radiotherapy (weeks 1-3 and 5-7). Patients then receive adjuvant chemotherapy consisting of cisplatin IV once every 4 weeks for 3 courses beginning on week 11, oral etoposide daily for 21 days every 4 weeks for 3 courses (weeks 11, 15, and 19), cyclophosphamide IV on days 1 and 2 with filgrastim (G-CSF) SQ daily for at least 10 days every 4 weeks for 8 courses (weeks 23-51), and vincristine IV on days 1, 8, and 15 every 4 weeks for 8 courses (weeks 23-51).	Drug: cyclophosphamide; Other Names: Cytoxan; CTX; NSC #026271; IND #7089; Radiation: radiation therapy; Drug: etoposide; Other Names: VP-16; VePesid; NSC #141540; IND #9197; Drug: vincristine sulfate; Other Names: VCR; Oncovin; NSC #067574; IND #7161; Drug: cisplatin; Other Names: CDDP; Platinol; Cis-diamminedichloroplatinum II; NSC #119875; Biological: filgrastim; Other Names: G-CSF; Granulocyte Colony-Stimulating Factor; r-metHuG-CSF; NSC #614629; Neupogen®
Experimental: Treatment 2, Etoposide, 35mg/m2/day; Patients begin treatment within 1 month of surgery. Patients receive 6 weeks of radiation therapy to the head and spine, with boosts to the posterior fossa and to sites of metastasis. Patients also receive 2 courses of oral etoposide once daily for 3 weeks concurrent with and immediately following radiotherapy (weeks 1-3 and 5-7). Patients then receive adjuvant chemotherapy consisting of cisplatin IV once every 4 weeks for 3 courses beginning on week 11, oral etoposide daily for 21 days every 4 weeks for 3 courses (weeks 11, 15, and 19), cyclophosphamide IV on days 1 and 2 with filgrastim (G-CSF) SQ daily for at least 10 days every 4 weeks for 8 courses (weeks 23-51), and vincristine IV on days 1, 8, and 15 every 4 weeks for 8 courses (weeks 23-51).	Drug: cyclophosphamide; Other Names: Cytoxan; CTX; NSC #026271; IND #7089; Radiation: radiation therapy; Drug: etoposide; Other Names: VP-16; VePesid; NSC #141540; IND #9197; Drug: vincristine sulfate; Other Names: VCR; Oncovin; NSC #067574; IND #7161; Drug: cisplatin; Other Names: CDDP; Platinol; Cis-diamminedichloroplatinum II; NSC #119875; Biological: filgrastim; Other Names: G-CSF; Granulocyte Colony-Stimulating Factor; r-metHuG-CSF; NSC #614629; Neupogen®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess the efficacy of oral etoposide at 50 mg/m2/day given concurrently with radiotherapy followed with dose intensive adjuvant chemotherapy in children with newly diagnosed high stage medulloblastoma	It is possible that unacceptably high levels of toxicity may arise. For this reason, there is a 3-stage stopping rule designed to allow the Study Coordinator to stop this study early if it appears that the true proportion of eligible patients who suffer unacceptable levels of toxicity exceeds 10%.	End of course 1 (week 10)

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Albert Moghrabi, MD, Hopital Sainte Justine

Publications and helpful links

General Publications

• Tarbell NJ, Friedman H, Polkinghorn WR, Yock T, Zhou T, Chen Z, Burger P, Barnes P, Kun L. High-risk medulloblastoma: a pediatric oncology group randomized trial of chemotherapy before or after radiation therapy (POG 9031). J Clin Oncol. 2013 Aug 10;31(23):2936-41. doi: 10.1200/JCO.2012.43.9984. Epub 2013 Jul 15.

Study record dates

Study Major Dates

• Study Start: November 1, 1998
• Primary Completion (Actual): October 1, 2007
• Study Completion (Actual): March 1, 2008

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: February 19, 2004
• First Posted (Estimate): February 20, 2004

Study Record Updates

• Last Update Posted (Estimate): July 25, 2014
• Last Update Submitted That Met QC Criteria: July 24, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Keywords: untreated childhood medulloblastoma
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Nervous System Neoplasms; Central Nervous System Neoplasms; Medulloblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Adjuvants, Immunologic; Cyclophosphamide; Etoposide; Cisplatin; Lenograstim; Vincristine
• Other Study ID Numbers: 9631; POG-9631 (Other Identifier: Pediatric Oncology Group); CDR0000066640 (Other Identifier: Clinical Trials.gov)