Combination Chemotherapy and Surgery With or Without Isotretinoin in Treating Young Patients With Neuroblastoma

Response- and Biology-Based Therapy for Intermediate-Risk Neuroblastoma

RATIONALE: Drugs used in chemotherapy, such as carboplatin, cyclophosphamide, etoposide, and doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Isotretinoin may help neuroblastoma cells become more like normal cells, and grow and spread more slowly. Giving combination chemotherapy before surgery may make the tumor smaller and make it more likely that the tumor can be surgically removed. It is not yet known what is the minimal amount of chemotherapy needed to achieve sufficient tumor shrinkage to control intermediate risk neuroblastoma and prevent tumor recurrence or metastases.

PURPOSE: This phase III trial is designed to reduce therapy for patients with favorable biology intermediate risk neuroblastoma by decreasing the number of chemotherapy cycles administered and by allowing for up to 50% residual tumor volume for patients with localized disease.

Study Overview

• Status: Completed
• Conditions: Neuroblastoma
• Intervention / Treatment: Drug: etoposide; Drug: cyclophosphamide; Drug: topotecan hydrochloride; Drug: doxorubicin hydrochloride; Drug: carboplatin; Drug: Isotretinoin; Procedure: Surgery; Drug: Filgrastim

Detailed Description

OBJECTIVES:

Primary

• Reduce therapy for patients with intermediate-risk neuroblastoma while maintaining a 3-year overall survival (OS) rate of ≥ 95% by using a response-based duration of therapy algorithm.
• Maintain an overall 3-year OS rate of ≥ 90% for patients within each group.
• Utilize loss of heterozygosity, prospectively, at 1p36 and 11q23 to refine risk-stratification and treatment assignment, allowing patients whose tumors lack these chromosomal abnormalities to receive a reduction in therapy, and compare the outcome with patients treated on COG-A3961.
• Reduce intensity of therapy for patients 365 to < 547 days (12-18 months) of age with stage 4 neuroblastoma and favorable biological features and maintain a 3-year event-free survival (EFS) rate consistent with that for patients < 1 year of age with stage 4 neuroblastoma treated on COG-A3961.
• Reduce intensity of therapy for patients 365 to < 547 days (12-18 months) of age with stage 3 MYCN-nonamplified but unfavorable histology neuroblastoma and maintain a 3-year EFS rate consistent with that for patients < 1 year of age with stage 3, MYCN-nonamplified, unfavorable histology neuroblastoma treated on COG-A3961.
• Reduce surgical morbidity for patients with stage 4S neuroblastoma by allowing for biopsy only, rather than complete surgical resection, of the primary tumor.
• Systematically study the outcome of patients with stage 4S neuroblastoma who are unable to undergo biopsy for biology-based risk assignment.
• Determine if the extent of surgical resection correlates with the maintenance of local control, EFS and/or OS rates, and surgical complication rate.

Secondary

• Determine the results of a standard retrieval approach for patients with residual disease after 8 courses of initial therapy.
• Determine the results of a standard retrieval approach for patients with progressive, nonmetastatic disease.
• Identify additional biological surrogate markers for disease relapse and/or metastatic progression.
• Describe the neurologic outcome of patients with paraspinal neuroblastoma primary tumors.
• Correlate surgical biopsy technique with adequacy of tissue acquisition for biologic studies and with complications associated with the biopsy procedure.
• Prospectively validate the prognostic ability of the International Neuroblastoma Risk Group image-defined risk factor system, and compare the institutional assessment of image-defined risk factors with that of central review.

OUTLINE: This is a multicenter study. Patients are assigned to 1 of 3 treatment groups by risk-stratification based on age, stage (INSS stage 2, 3, 4, or 4S), MYCN status (amplified vs not amplified), histopathologic classification, tumor DNA index, and allelic status at chromosome bands 11q23 and 1p36.

• Initial chemotherapy: Courses of initial chemotherapy are administered every 21 days according to group assignment as outlined below:

  • Course 1: Patients receive carboplatin IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1-3.
  • Course 2: Patients receive carboplatin IV over 1 hour, cyclophosphamide IV over 1 hour, and doxorubicin hydrochloride IV over 15 minutes on day 1.
  • Course 3: Patients receive cyclophosphamide IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1-3.
  • Course 4: Patients receive carboplatin IV over 1 hour and doxorubicin hydrochloride IV over 15 minutes on day 1 and etoposide IV over 1 hour on days 1-3.
  • Course 5: Patients receive cyclophosphamide IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1-3.
  • Course 6: Patients receive carboplatin IV over 1 hour, cyclophosphamide IV over 1 hour, and doxorubicin hydrochloride IV over 15 minutes on day 1.
  • Course 7: Patients receive carboplatin IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1-3.

  • Course 8: Patients receive cyclophosphamide IV over 1 hour and doxorubicin hydrochloride IV over 15 minutes on day 1.

    • Group 2: Patients receive 2 courses of initial chemotherapy. Patients with a partial response (PR) (50-90% reduction in volume) to chemotherapy proceed to observation. Patients without a PR receive 2-6 additional courses of chemotherapy (beginning with course 3). Patients who do not achieve a PR after additional chemotherapy proceed to retrieval chemotherapy.
    • Group 3: Patients receive 4 courses of initial chemotherapy. Patients with a PR after chemotherapy proceed to observation. Patients without a PR receive 2-4 additional courses of chemotherapy (beginning with course 5). Patients who do not achieve a PR after additional chemotherapy proceed to retrieval chemotherapy.
    • Group 4: Patients receive 8 courses of initial chemotherapy. Patients under 12 months of age with stage 3, 4, or 4S disease who achieve a very good PR (VGPR) (> 90% reduction in the volume of the primary tumor and resolution of metastatic disease, with the exception of liver and skin metastases) to chemotherapy proceed to observation. Patients 12-18 months of age with stage 3 or 4 disease [age 365 to < 547 days at diagnosis, INSS stage 3, MYCN-NA, unfavorable histology, any ploidy and patients age 365 to < 547 days at diagnosis, INSS stage 4, MYCN-NA, favorable histology, DI > 1] who achieve a VGPR proceed to isotretinoin therapy. Patients who do not achieve a VGPR after 8 courses of initial chemotherapy +/- surgery will proceed to retrieval chemotherapy with cyclophosphamide/topotecan for 2-6 courses until a VGPR can be achieved with a combination of chemotherapy and surgery.

• Retrieval chemotherapy*: Patients receive cyclophosphamide IV over 30 minutes and topotecan IV over 30 minutes on days 1-5. Treatment repeats every 21 days for up to 6 courses.

  • Groups 2 and 3: Patients with a PR after 2-6 courses of retrieval chemotherapy proceed to observation. Patients without a PR after 2-6 courses of retrieval chemotherapy are removed from protocol therapy.
  • Group 4: Patients under 12 months of age with stage 4 disease with a VGPR after retrieval chemotherapy proceed to observation. Patients 12-18 months of age with stage 3 or 4 disease who achieve a VGPR after retrieval chemotherapy proceed to isotretinoin therapy. Patients who do not achieve a VGPR after retrieval chemotherapy are removed from protocol therapy.

Group 4 patients who develop progressive, non-metastatic disease within 3 years of study enrollment will also receive retrieval chemotherapy with cyclophosphamide and topotecan.

NOTE: *Patients who have previously received cyclophosphamide and topotecan to achieve first PR/VGPR are not eligible for this Retrieval Therapy.

• Surgery: With the exception of patients with INSS 4S disease, patients undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished. Reassessment for definitive surgery (for patients who undergo biopsy only or partial resection at diagnosis) is made at the completion of scheduled chemotherapy (after course 2 for group 2, after course 4 for group 3, and after course 8 for group 4).
• Isotretinoin therapy: Beginning 3-4 weeks after completion of chemotherapy or 2 weeks post-operatively (for patients who undergo surgical resection), patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up periodically for up to 10 years.

• Study Type: Interventional
• Enrollment (Actual): 464
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Children's Hospital at Westmead
  • Queensland
    • Brisbane, Queensland, Australia, 4029
      • Royal Children's Hospital
  • South Australia
    • North Adelaide, South Australia, Australia, 5006
      • Women's and Children's Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6001
      • Princess Margaret Hospital for Children
• Canada
  • Quebec, Canada, G1V 4G2
    • Centre Hospitalier Universitaire de Quebec
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Alberta Children's Hospital
    • Edmonton, Alberta, Canada, T6G 1Z2
      • University of Alberta Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • Children's & Women's Hospital of British Columbia
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Newfoundland and Labrador
    • St. John's, Newfoundland and Labrador, Canada, A1B 3V6
      • Janeway Children's Health and Rehabilitation Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3J 3G9
      • IWK Health Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster Children's Hospital at Hamilton Health Sciences
    • Kingston, Ontario, Canada, K7L 2V7
      • Cancer Centre of Southeastern Ontario At Kingston General Hospital
    • London, Ontario, Canada, N6A 5W9
      • Children's Hospital of Western Ontario
    • 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
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4T 7T1
      • Allan Blair Cancer Centre at Pasqua Hospital
    • Saskatoon, Saskatchewan, Canada, S7N 4H4
      • Saskatoon Cancer Centre at the University of Saskatchewan
• Netherlands
  • Nijmegen, Netherlands, 6500
    • Universitair Medisch Centrum St. Radboud - Nijmegen
• New Zealand
  • Auckland, New Zealand, 1
    • Starship Children's Health
  • Christchurch, New Zealand, 8140
    • Christchurch Hospital
• Puerto Rico
  • Santurce, Puerto Rico, 00912
    • San Jorge Children's Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • UAB Comprehensive Cancer Center
    • Mobile, Alabama, United States, 36604
      • University of South Alabama Mitchell Cancer Institute
  • Arizona
    • Phoenix, Arizona, United States, 85016-7710
      • Phoenix Children's Hospital
    • Tucson, Arizona, United States, 85724-5024
      • Arizona Cancer Center at University of Arizona Health Sciences Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
  • California
    • Downey, California, United States, 90027
      • Southern California Permanente Medical Group
    • Duarte, California, United States, 91010-3000
      • City of Hope Comprehensive Cancer Center
    • Loma Linda, California, United States, 92354
      • Loma Linda University Cancer Institute at Loma Linda University Medical Center
    • Long Beach, California, United States, 90801
      • Jonathan Jaques Children's Cancer Center at Miller Children's Hospital
    • Los Angeles, California, United States, 90027
      • Childrens Hospital Los Angeles
    • Madera, California, United States, 93638-8762
      • Children's Hospital Central California
    • Oakland, California, United States, 94609
      • Children's Hospital and Research Center Oakland
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Palo Alto, California, United States, 95798
      • Lucile Packard Children's Hospital at Stanford University Medical Center
    • Sacramento, California, United States, 95816
      • Sutter Cancer Center
    • Sacramento, California, United States, 95817
      • University of California Davis Cancer Center
    • Sacramento, California, United States, 95825
      • Kaiser Permanente Medical Center - Oakland
    • San Diego, California, United States, 92123-4282
      • Rady Children's Hospital - San Diego
    • San Francisco, California, United States, 94115
      • UCSF Helen Diller Family Comprehensive Cancer Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Center for Cancer and Blood Disorders
    • Denver, Colorado, United States, 80218
      • Presbyterian - St. Luke's Medical Center
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center
    • New Haven, Connecticut, United States, 06520-8028
      • Yale Cancer Center
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfred I. DuPont Hospital for Children
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-2970
      • Children's National Medical Center
    • Washington, District of Columbia, United States, 20007
      • Lombardi Comprehensive Cancer Center at Georgetown University Medical Center
    • Washington, District of Columbia, United States, 20307-5001
      • Walter Reed Army Medical Center
  • Florida
    • Fort Lauderdale, Florida, United States, 33316
      • Broward General Medical Center Cancer Center
    • Fort Myers, Florida, United States, 33901
      • Lee Cancer Care of Lee Memorial Health System
    • Gainesville, Florida, United States, 32610-0232
      • University of Florida Shands Cancer Center
    • Hollywood, Florida, United States, 33021
      • Memorial Cancer Institute at Memorial Regional Hospital
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center - Miami
    • Miami, Florida, United States, 33176
      • Baptist-South Miami Regional Cancer Program
    • Orlando, Florida, United States, 32803-1273
      • Florida Hospital Cancer Institute at Florida Hospital Orlando
    • Orlando, Florida, United States, 32806
      • Nemours Children's Clinic - Orlando
    • Orlando, Florida, United States, 32806
      • M.D. Anderson Cancer Center at Orlando
    • Pensacola, Florida, United States, 32504
      • Nemours Children's Clinic - Pensacola
    • Saint Petersburg, Florida, United States, 33701
      • All Children's Hospital
    • Tampa, Florida, United States, 33607
      • St. Joseph's Cancer Institute at St. Joseph's Hospital
    • West Palm Beach, Florida, United States, 33407
      • Kaplan Cancer Center at St. Mary's Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus
    • Augusta, Georgia, United States, 30912-3730
      • MBCCOP - Medical College of Georgia Cancer Center
    • Savannah, Georgia, United States, 31403-3089
      • Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Cancer Research Center of Hawaii
    • Tripler AMC, Hawaii, United States, 96859-5000
      • Tripler Army Medical Center
  • Idaho
    • Boise, Idaho, United States, 83712-6297
      • Mountain States Tumor Institute at St. Luke's Regional Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Cancer Research Center
    • Chicago, Illinois, United States, 60612-7243
      • University of Illinois Cancer Center
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital - Chicago
    • Maywood, Illinois, United States, 60153
      • Cardinal Bernardin Cancer Center at Loyola University Medical Center
    • Oak Lawn, Illinois, United States, 60453
      • Keyser Family Cancer Center at Advocate Hope Children's Hospital
    • Park Ridge, Illinois, United States, 60068-1174
      • Advocate Lutheran General Cancer Care Center
    • Peoria, Illinois, United States, 61637
      • Saint Jude Midwest Affiliate
    • Springfield, Illinois, United States, 62794-9677
      • Simmons Cooper Cancer Institute
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5289
      • Indiana University Melvin and Bren Simon Cancer Center
  • Iowa
    • Des Moines, Iowa, United States, 50309
      • Blank Children's Hospital
    • Iowa City, Iowa, United States, 52242-1002
      • Holden Comprehensive Cancer Center at University of Iowa
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0093
      • Lucille P. Markey Cancer Center at University of Kentucky
    • Louisville, Kentucky, United States, 40232
      • Kosair Children's Hospital
  • Louisiana
    • Alexandria, Louisiana, United States, 71315-3198
      • Tulane Cancer Center Office of Clinical Research
  • Maine
    • Bangor, Maine, United States, 04401
      • CancerCare of Maine at Eastern Maine Medical Center
    • Scarborough, Maine, United States, 04074-9308
      • Maine Children's Cancer Program at Barbara Bush Children's Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    • Baltimore, Maryland, United States, 21215
      • Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
    • Baltimore, Maryland, United States, 21201
      • Greenebaum Cancer Center at University of Maryland Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02111
      • Floating Hospital for Children at Tufts - New England Medical Center
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0286
      • C.S. Mott Children's Hospital at University of Michigan Medical Center
    • Detroit, Michigan, United States, 48201-1379
      • Barbara Ann Karmanos Cancer Institute
    • Flint, Michigan, United States, 48503
      • Hurley Medical Center
    • Grand Rapids, Michigan, United States, 49503
      • Helen DeVos Children's Hospital at Spectrum Health
    • Grosse Pointe Woods, Michigan, United States, 48236
      • Van Elslander Cancer Center at St. John Hospital and Medical Center
    • Kalamazoo, Michigan, United States, 49007-5381
      • CCOP - Kalamazoo
    • Lansing, Michigan, United States, 48910
      • Breslin Cancer Center at Ingham Regional Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospitals and Clinics of Minnesota - Minneapolis
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center at University of Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216-4505
      • University of Mississippi Cancer Clinic
  • Missouri
    • Columbia, Missouri, United States, 65203
      • Ellis Fischel Cancer Center at University of Missouri - Columbia
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
    • Saint Louis, Missouri, United States, 63104
      • Cardinal Glennon Children's Hospital
    • Saint Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
  • Nebraska
    • Omaha, Nebraska, United States, 68114-4113
      • Children's Hospital
    • Omaha, Nebraska, United States, 68198-6805
      • UNMC Eppley Cancer Center at the University of Nebraska Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89109-2306
      • CCOP - Nevada Cancer Research Foundation
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756-0002
      • Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center Cancer Center
    • Morristown, New Jersey, United States, 07962
      • Overlook Hospital
    • New Brunswick, New Jersey, United States, 08901
      • Saint Peter's University Hospital
    • New Brunswick, New Jersey, United States, 08903
      • Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
    • Paterson, New Jersey, United States, 07503
      • St. Joseph's Hospital and Medical Center
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131-5636
      • University of New Mexico Cancer Center
  • New York
    • Albany, New York, United States, 12208-3419
      • Albany Medical Center Hospital
    • Bronx, New York, United States, 10461
      • Albert Einstein Cancer Center at Albert Einstein College of Medicine
    • Brooklyn, New York, United States, 11219
      • Maimonides Cancer Center at Maimonides Medical Center
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
    • New Hyde Park, New York, United States, 11040
      • Schneider Children's Hospital
    • New York, New York, United States, 10016
      • NYU Cancer Institute at New York University Medical Center
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
    • Rochester, New York, United States, 14642
      • James P. Wilmot Cancer Center at University of Rochester Medical Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Hospital
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Mission Hospitals - Memorial Campus
    • Chapel Hill, North Carolina, United States, 27599-7295
      • Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
    • Charlotte, North Carolina, United States, 28232-2861
      • Blumenthal Cancer Center at Carolinas Medical Center
    • Charlotte, North Carolina, United States, 28233-3549
      • Presbyterian Cancer Center at Presbyterian Hospital
    • Durham, North Carolina, United States, 27710
      • Duke Comprehensive Cancer Center
    • Winston-Salem, North Carolina, United States, 27157-1096
      • Wake Forest University Comprehensive Cancer Center
  • Ohio
    • Akron, Ohio, United States, 44308-1062
      • Akron Children's Hospital
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
    • Cleveland, Ohio, United States, 44106-5000
      • Rainbow Babies and Children's Hospital
    • Columbus, Ohio, United States, 43205-2696
      • Nationwide Children's Hospital
    • Dayton, Ohio, United States, 45404-1815
      • Dayton Children's - Dayton
    • Toledo, Ohio, United States, 43606
      • Toledo Hospital
    • Toledo, Ohio, United States, 43608
      • Mercy Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma University Cancer Institute
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Knight Cancer Institute At Oregon Health and Science University
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Hospital and Health Center and Children's Hospital
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18017
      • Lehigh Valley Hospital - Muhlenberg
    • Danville, Pennsylvania, United States, 17822-0001
      • Geisinger Cancer Institute at Geisinger Health
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Children's Hospital
    • Philadelphia, Pennsylvania, United States, 19134-1095
      • St. Christopher's Hospital for Children
    • Philadelphia, Pennsylvania, United States, 19104-9786
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh of UPMC
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital Comprehensive Cancer Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Hollings Cancer Center at Medical University of South Carolina
    • Columbia, South Carolina, United States, 29203
      • Palmetto Health South Carolina Cancer Center
    • Greenville, South Carolina, United States, 29605
      • Greenville Hospital Cancer Center
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57117-5039
      • Sanford Cancer Center at Sanford USD Medical Center
  • Tennessee
    • Chattanooga, Tennessee, United States, 37403
      • T.C. Thompson Children's Hospital
    • Knoxville, Tennessee, United States, 37901
      • East Tennessee Children's Hospital
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
    • Nashville, Tennessee, United States, 37232-6838
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • Amarillo, Texas, United States, 79106
      • Texas Tech University Health Sciences Center School of Medicine - Amarillo
    • Austin, Texas, United States, 78723
      • Dell Children's Medical Center of Central Texas
    • Corpus Christi, Texas, United States, 78411
      • Driscoll Children's Hospital
    • Dallas, Texas, United States, 75230
      • Medical City Dallas Hospital
    • Dallas, Texas, United States, 75390
      • Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center - Fort Worth
    • Houston, Texas, United States, 77030-2399
      • Baylor University Medical Center - Houston
    • Lubbock, Texas, United States, 79410
      • Covenant Children's Hospital
    • San Antonio, Texas, United States, 78229-3993
      • Methodist Children's Hospital of South Texas
    • San Antonio, Texas, United States, 78207
      • University of Texas Health Science Center at San Antonio
    • Temple, Texas, United States, 76508
      • CCOP - Scott and White Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84113-1100
      • Primary Children's Medical Center
  • Vermont
    • Burlington, Vermont, United States, 05401
      • Fletcher Allen Health Care - University Health Center Campus
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Cancer Center
    • Falls Church, Virginia, United States, 22042-3300
      • Inova Fairfax Hospital
    • Norfolk, Virginia, United States, 23507-1971
      • Children's Hospital of The King's Daughters
    • Portsmouth, Virginia, United States, 23708-2197
      • Naval Medical Center - Portsmouth
    • Richmond, Virginia, United States, 23298-0037
      • Virginia Commonwealth University Massey Cancer Center
    • Roanoke, Virginia, United States, 24014
      • Carilion Medical Center for Children at Roanoke Community Hospital
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center - Seattle
    • Spokane, Washington, United States, 99220-2555
      • Providence Cancer Center at Sacred Heart Medical Center
    • Tacoma, Washington, United States, 98405
      • Mary Bridge Children's Hospital and Health Center - Tacoma
    • Tacoma, Washington, United States, 98431
      • Madigan Army Medical Center - Tacoma
  • West Virginia
    • Charleston, West Virginia, United States, 25302
      • West Virginia University Health Sciences Center - Charleston
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54307-3508
      • St. Vincent Hospital Regional Cancer Center
    • Madison, Wisconsin, United States, 53792-6164
      • University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic - Marshfield Center
    • Milwaukee, Wisconsin, United States, 53226
      • Midwest Children's Cancer Center at Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 12 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed neuroblastoma, ganglioneuroblastoma, or ganglioneuroma/maturing subtype

  • Newly diagnosed disease
  • Intermediate-risk disease
  • Needle biopsies or involved bone marrow are not sufficient for INPC histologic classification

• Meets 1 of the following criteria:

  • Group 2

    • International Neuroblastoma Staging System (INSS) stage 2A/2B; < 50% resected or biopsy only; ≤ 12 years of age; MYCN-not amplified (NA); any histology and ploidy; normal 1p and 11q
    • INSS stage 3; age < 365 days; MYCN-NA; favorable histology (FH); hyperdiploid (DI) > 1; normal 1p and 11q
    • INSS stage 3; 365 days to 12 years of age; MYCN-NA; FH; normal 1p and 11q
    • INSS stage 4S; age < 365 days; MYCN-NA; FH; DI >1; normal 1p and 11q; clinically symptomatic

  • Group 3

    • INSS stage 2A/2B; < 50% resected or biopsy only; ≤ 12 years of age; MYCN-NA; any histology and ploidy; 1p loss of heterozygosity (LOH) and/or unb11q LOH (or data missing for either)
    • INSS stage 3; age < 365 days; MYCN-NA; FH; DI > 1; 1p LOH and/or unb11q LOH (or data missing for either)
    • INSS stage 3; age < 365 days; MYCN-NA; DI = 1 and/or unfavorable histology (UH); normal 1p and 11q
    • INSS stage 3; 365 days to 12 years of age; MYCN-NA; FH; 1p LOH and/or unb11q LOH (or data missing for either)
    • INSS stage 4; age < 365 days; MYCN-NA; FH; DI > 1; normal 1p and 11q
    • INSS stage 4S; age < 365 days; MYCN-NA; either UH and any ploidy or FH and DI = 1; normal 1p and 11q
    • INSS stage 4S; age < 365 days; MYCN-NA; FH; DI > 1; 1p LOH and/or unb11q LOH (or data missing for either); clinically symptomatic

  • Group 4

    • INSS stage 3; age < 365 days; MYCN-NA; DI = 1 and/or UH; 1p LOH and/or unb11q LOH (or data missing for either)
    • INSS stage 3; age 365 to < 547 days; MYCN-NA; UH; any ploidy; any 1p and 11q
    • INSS stage 4, age < 365 days; MYCN-NA; DI = 1 and/or UH; any 1p and 11q
    • INSS stage 4; age < 365 days; MYCN-NA; FH; DI > 1; 1p LOH and/or unb11q LOH (or data missing for either)
    • INSS stage 4; age 365 to < 547 days; MYCN-NA; FH; DI > 1; any 1p and 11q
    • INSS stage 4S; age < 365 days; MYCN-NA; UH and any ploidy or FH and DI = 1; 1p LOH and/or unb11q LOH (or data missing for either)

    • INSS stage 4S; age < 365 days; unknown or incomplete biologic features

      8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim.

Patients < 12 months of age with stg 3, 4, or 4S disease who achieve a very good PR (VGPR) to chemo (with the exception of resolution of skin or liver metastases in stage 4S patients) proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.

• Must already be enrolled on protocol COG-ANBL00B1

  • Simultaneous enrollment on COG-ANBL00B1 and this study allowed for clinical situations in which emergent treatment may be indicated including, but not limited to, the following criteria:

    • Epidural or intraspinal tumors with existing or impending neurologic impairment
    • Periorbital or calvarial-based lesions with existing or impending cranial nerve impairment
    • Anatomic or mechanical compromise of critical organ function by tumor (e.g., abdominal compartment syndrome, urinary obstruction)
    • Asymptomatic but, in the opinion of the treating physician, it is in the patient's best interest to begin chemotherapy immediately due to impending risk of neurologic impairment or organ dysfunction

• If patient receives study chemotherapy prior to undergoing diagnostic biopsy, the biopsy must be performed within 96 hours of beginning study therapy

  • The only exception to this requirement is for patients with stage 4S disease who are considered too ill to undergo a diagnostic procedure will be waived the requirement for diagnostic tissue submission but will still need to be enrolled on COG-ANBL00B1

    • For patients with stage 4S disease who are very ill and in whom an open biopsy to obtain tissue for diagnosis and biologic studies is considered medically contraindicated, every effort should be made to obtain some tumor tissue by either fine-needle aspiration of a metastatic site of disease and/or sampling of involved bone marrow, so that this tumor sample can be submitted for MYCN determination

• Patients who require emergent therapy, either prior to the diagnostic biopsy or before biology features are available, can be enrolled simultaneously on COG-ANBL00B1 and COG-ANBL0531 to receive emergent protocol therapy

  • In emergent circumstances, COG-ANBL0531 protocol therapy may be initiated prior to enrollment on study as long as the patient has neuroblastoma by clinical diagnosis, all other COG-ANBL0531 eligibility criteria are met, and the COG-ANBL0531 Initial Therapy consent has been signed prior to starting protocol therapy; in this circumstance ANBL0531 enrollment must occur within 4 working days of starting protocol therapy

  • Clinical situations in which emergent enrollment and treatment may be indicated include, but are not limited to, the following circumstances:

    • Epidural or intraspinal tumors with existing or impending neurologic impairment
    • Periorbital or calvarial-based lesions with existing or impending cranial nerve impairment
    • Anatomic or mechanical compromise of critical organ function by tumor (e.g., abdominal compartment syndrome, urinary obstruction)
    • Evolving hepatomegaly in infants less than 2 months of age

PATIENT CHARACTERISTICS:

• See Disease Characteristics

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No other prior chemotherapy or radiotherapy with the exception of dexamethasone
• No participation in another COG study with tumor therapeutic intent

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 2 (chemotherapy, surgery); 2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery.	Drug: etoposide; Given orally; Other Names: VP-16; VePesid; NSC #141540; Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; NSC #26271; Drug: topotecan hydrochloride; Given IV; Other Names: SKF-104864; Hycamtin; NSC #60969; Drug: doxorubicin hydrochloride; Given IV; Other Names: Adriamycin; NSC #123127; Drug: carboplatin; Given IV; Other Names: Paraplatin; NSC #241240; Procedure: Surgery; With the exception of patients with INSS 4S disease, patients undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished.; Drug: Filgrastim; Administered subcutaneously or by IV beginning 24-48 hrs after the last dose of chemotherapy & continuing daily until the ANC is greater than or equal to 1500 following the myelosuppressive nadir . Supportive care given to stimulate neutrophil recovery following chemotherapy and to shorten the duration of chemotherapy-induced neutropenia. On ANBL0531 the use of filgrastim was required for patients less than 60 days of age and was optional for other patients.; Other Names: Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen, NSC #614629
Experimental: Group 3 (chemotherapy, surgery); 4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Drug: etoposide; Given orally; Other Names: VP-16; VePesid; NSC #141540; Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; NSC #26271; Drug: topotecan hydrochloride; Given IV; Other Names: SKF-104864; Hycamtin; NSC #60969; Drug: doxorubicin hydrochloride; Given IV; Other Names: Adriamycin; NSC #123127; Drug: carboplatin; Given IV; Other Names: Paraplatin; NSC #241240; Procedure: Surgery; With the exception of patients with INSS 4S disease, patients undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished.; Drug: Filgrastim; Administered subcutaneously or by IV beginning 24-48 hrs after the last dose of chemotherapy & continuing daily until the ANC is greater than or equal to 1500 following the myelosuppressive nadir . Supportive care given to stimulate neutrophil recovery following chemotherapy and to shorten the duration of chemotherapy-induced neutropenia. On ANBL0531 the use of filgrastim was required for patients less than 60 days of age and was optional for other patients.; Other Names: Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen, NSC #614629
Experimental: Group 4 (chemotherapy, surgery, antineoplastic therapy); 8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients < 12 months of age with stg 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) to chemo proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Drug: etoposide; Given orally; Other Names: VP-16; VePesid; NSC #141540; Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; NSC #26271; Drug: topotecan hydrochloride; Given IV; Other Names: SKF-104864; Hycamtin; NSC #60969; Drug: doxorubicin hydrochloride; Given IV; Other Names: Adriamycin; NSC #123127; Drug: carboplatin; Given IV; Other Names: Paraplatin; NSC #241240; Drug: Isotretinoin; Given orally; Other Names: Amnesteem; Claravis; Sotret; Accutane; 13-cis-retinoic acid; RO-43; 780; NSC#329481; Procedure: Surgery; With the exception of patients with INSS 4S disease, patients undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished.; Drug: Filgrastim; Administered subcutaneously or by IV beginning 24-48 hrs after the last dose of chemotherapy & continuing daily until the ANC is greater than or equal to 1500 following the myelosuppressive nadir . Supportive care given to stimulate neutrophil recovery following chemotherapy and to shorten the duration of chemotherapy-induced neutropenia. On ANBL0531 the use of filgrastim was required for patients less than 60 days of age and was optional for other patients.; Other Names: Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen, NSC #614629
Experimental: Non-intermediate risk enrolled on intermediate risk trial; The no treatment group assignment patients may have received some treatment on ANBL0531 but they were not evaluable on this study due to being non-intermediate risk and hence did not receive a treatment assignment on ANBL0531.	Procedure: Surgery; With the exception of patients with INSS 4S disease, patients undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS) Rates	OS time is calculated from date of enrollment until death, or until last contact if the patient is alive.	3 years
Definitive Determination of the Prognostic Ability of 1p and 11q	Addressed by a descriptive comparison of the EFS and OS rates for patients with 1p loss vs without 1p loss, and for those with unbalanced 11q vs normal 11q.	At baseline
Comparison Between Reduce Intensity of Therapy for Patients With Stage 4 Neuroblastoma and Favorable Biological Features and Patients < 1 Year of Age With Stage 4 Neuroblastoma Treated on COG-A3961	Addressed by the interim stopping rule and the comparison, by INSS stage, to the historical EFS rate of the analogous cohort of patients < 1 yrs of age.	Up to 3 years
Comparison Between Reduce Intensity of Therapy for Patients With Unfavorable Histology Neuroblastoma and Patients Unfavorable Histology Neuroblastoma Treated on COG-A3961	Addressed by the interim stopping rule and the comparison, by INSS stage, to the historical EFS rate of the analogous cohort of patients < 1 yrs of age	Up to 3 years
Reduced Surgical Morbidity for Patients With Stage 4S Neuroblastoma	Descriptive analyses of the proportion of stage 4S infants that experience a surgical or post-operative event.	Up to 3 years
Outcome of Patients With Stage 4S Neuroblastoma Who Are Unable to Undergo Biopsy for Biology-based Risk Assignment	Kaplan-Meier curves and lifetables of Event Free Survival (EFS) and Overall Survival (OS) rates will be generated to describe the outcome of the stage 4S infants unable to undergo biopsy.	From baseline to up to 10 years
Correlation Between Extent of Surgical Resection With the Maintenance of Local Control, Event Free Survival (EFS)	To test the predictive ability of the extent of surgical resection for EFS, log-rank tests will be performed comparing complete surgical resection vs. without complete surgical resection.	Up to 10 years
Correlation Between Extent of Surgical Resection With the Maintenance of Local Control, Overall Survival (OS) Rates	To test the predictive ability of the extent of surgical resection for OS, log-rank tests will be performed comparing complete surgical resection vs. without complete surgical resection.	Up to 10 years
Correlation Between Extent of Surgical Resection With the Maintenance of Local Control, Surgical Complication Rate	To test for the association of the extent of surgical resection (CR vs <CR) with surgical complications rate (complications of any kind vs no complications at all), a chi-square test will be performed.	Up to 10 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Second-event-free Survival (E2FS)	E2FS (from time of first event) will be calculated to describe the outcome for patients who have a first progressive, non-metastatic event during Observation and then receive protocol retrieval therapy.	From the time of the first progressive, non-metastatic event until the subsequent occurrence of relapse, progressive disease, secondary malignancy, or death; up to 3 years
Second-Overall Survival	OS (from the time of first event) will be calculated to describe the outcome for patients who have a first progressive, non-metastatic event during Observation and then receive protocol retrieval therapy.	From the time of the first progressive, non-metastatic event; up to 3 years
Biological Surrogate Markers	Multivariable analyses will be performed to identify variables of prognostic interest.	At baseline and surgery
Neurologic Symptoms	Percentage of patients with neurologic symptoms will be calculated. Includes patients with paraspinal or intraspinal tumors, including epidural tumors with or without spinal cord compression. Neurologic symptoms include back or extremities neurologic symptoms, motor deficit, abnormal sensation, abnormal bladder/bowel sphincteric function, chronic pain in back or extremities, scoliosis, kyphosis, or clinically relevant/functional abnormality in size or contour of leg or foot.	At baseline
Association Between Surgical Biopsy Technique With Adequacy of Tissue Acquisition for Biologic Studies, and With Complications Associated With the Biopsy Procedure	A chi-square test will be performed.	During and after surgery
Image Defined Risk Factor (IDRF)	Percentage of patients with presence of one or more IDRFs will be calculated. IDRFs describe anatomic features which may make surgical resection more difficult.	At baseline

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Clare Twist, MD, Lucile Packard Children's Hospital at Stanford University Medical Center; Study Chair: Mary Lou Schmidt, MD, University of Illinois at Chicago

Publications and helpful links

General Publications

• Twist CJ, Schmidt ML, Naranjo A, London WB, Tenney SC, Marachelian A, Shimada H, Collins MH, Esiashvili N, Adkins ES, Mattei P, Handler M, Katzenstein H, Attiyeh E, Hogarty MD, Gastier-Foster J, Wagner E, Matthay KK, Park JR, Maris JM, Cohn SL. Maintaining Outstanding Outcomes Using Response- and Biology-Based Therapy for Intermediate-Risk Neuroblastoma: A Report From the Children's Oncology Group Study ANBL0531. J Clin Oncol. 2019 Dec 1;37(34):3243-3255. doi: 10.1200/JCO.19.00919. Epub 2019 Aug 6.
• Twist CJ, Naranjo A, Schmidt ML, Tenney SC, Cohn SL, Meany HJ, Mattei P, Adkins ES, Shimada H, London WB, Park JR, Matthay KK, Maris JM. Defining Risk Factors for Chemotherapeutic Intervention in Infants With Stage 4S Neuroblastoma: A Report From Children's Oncology Group Study ANBL0531. J Clin Oncol. 2019 Jan 10;37(2):115-124. doi: 10.1200/JCO.18.00419. Epub 2018 Nov 16.

Helpful Links

• Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive
• Maintaining Outstanding Outcomes Using Response- and Biology-Based Therapy for Intermediate-Risk Neuroblastoma: A Report From the Children's Oncology Group Study ANBL0531

Study record dates

Study Major Dates

• Study Start (Actual): October 8, 2007
• Primary Completion (Actual): June 30, 2014
• Study Completion (Actual): June 30, 2021

Study Registration Dates

• First Submitted: July 10, 2007
• First Submitted That Met QC Criteria: July 10, 2007
• First Posted (Estimate): July 11, 2007

Study Record Updates

• Last Update Posted (Actual): July 6, 2021
• Last Update Submitted That Met QC Criteria: July 1, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: disseminated neuroblastoma; localized unresectable neuroblastoma; stage 4S neuroblastoma; regional neuroblastoma; localized resectable neuroblastoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Neuroblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Topoisomerase I Inhibitors; Cyclophosphamide; Carboplatin; Etoposide; Lenograstim; Doxorubicin; Liposomal doxorubicin; Topotecan; Isotretinoin
• Other Study ID Numbers: ANBL0531; COG-ANBL0531 (Other Identifier: Children's Oncology Group); NCI-2009-00400 (Other Identifier: CTRP (Clinical Trial Reporting Program))