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A Randomized Trial of the European and American Osteosarcoma Study Group to Optimize Treatment Strategies for Resectable Osteosarcoma Based on Histological Response to Pre-Operative Chemotherapy (IND# 12697)

Phase 3
5 Years
40 Years
Open (Enrolling)
Localized Osteosarcoma, Metastatic Osteosarcoma

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Trial Information

A Randomized Trial of the European and American Osteosarcoma Study Group to Optimize Treatment Strategies for Resectable Osteosarcoma Based on Histological Response to Pre-Operative Chemotherapy (IND# 12697)


I. Compare whether adjuvant maintenance therapy comprising doxorubicin, cisplatin, and
high-dose methotrexate (MAP) alone vs MAP combined with ifosfamide and etoposide improves
event-free survival of patients with resectable high-grade osteosarcoma who achieve a poor
histological response (HR) to neoadjuvant induction therapy comprising MAP.

II. Compare whether adjuvant maintenance therapy comprising MAP alone vs MAP and
PEG-interferon alfa-2b improves event-free survival of patients with resectable high-grade
osteosarcoma who achieve a good HR to neoadjuvant induction therapy comprising MAP.


I. Compare overall survival of patients treated with these regimens. II. Compare short- and
long-term toxicity of these regimens in these patients. III. Compare quality of life of
patients treated with these regimens. IV. Compare event-free survival and overall survival
of patients with localized osteosarcoma treated with these regimens.

V. Correlate biological or clinical changes with histological response and outcomes in
patients treated with these regimens.

VI. Determine outcomes of patients treated with these regimens.

OUTLINE: This is a randomized, controlled, multicenter study.

INDUCTION THERAPY: (MAP; weeks 1-10) Patients receive doxorubicin IV continuously over 48
hours on days 1-2 and cisplatin IV over 4 hours on days 1 and 2 in weeks 1 and 6. Patients
also receive high-dose methotrexate (MTX)* IV over 4 hours on day 1 in weeks 4, 5, 9, and
10. Patients then proceed to surgery.

NOTE: *Patients must receive >= 2 but =< 6 doses of high-dose MTX.

SURGERY: Patients undergo amputation or limb salvage surgery in week 11. Tumor tissue is
evaluated for histological response to induction therapy. Patients whose tumor is not
amenable to macroscopically complete surgical resection undergo radiotherapy and/or other
investigational therapy off study. Patients who undergo macroscopically complete surgical
resection of the primary tumor or metastases AND who have no disease progression or
unacceptable toxicity proceed to maintenance therapy.

MAINTENANCE THERAPY: Patients are assigned to 1 of 2 groups according to histological
response (good [< 10% viable tumor] vs poor [≥ 10% viable tumor]). Patients in each group
are stratified according to site of primary tumor and presence of metastases.

GROUP 1: (good histological response) Patient are randomized to 1 of 2 treatment arms within
35 days after surgery.

ARM I: (MAP; weeks 12-29) Patients receive doxorubicin IV continuously over 48 hours on days
1-2 in weeks 12, 17, 22, and 26 and cisplatin IV over 4 hours on days 1 and 2 in weeks 12
and 17. Patients also receive high-dose MTX IV over 4 hours on day 1 in weeks 15, 16, 20,
21, 24, 25, 28, and 29.

ARM II: (MAPifn; weeks 12-104) Patients receive doxorubicin, cisplatin, and high-dose MTX as
in arm I. Patients than receive PEG-interferon alfa-2b subcutaneously once daily on day 1 in
weeks 30-104.

GROUP 2: (poor histological response) Patients are randomized to 1 of 2 treatment arms
within 35 days after surgery.

ARM I: (MAP; weeks 12-29) Patients receive doxorubicin, cisplatin, and high-dose MTX as in
group 1 arm I.

ARM II: (MAPIE; weeks 12-40) Patients receive doxorubicin IV continuously over 48 hours on
days 1-2 in weeks 12, 20, 28, and 36 and cisplatin IV over 4 hours on days 1 and 2 in weeks
12 and 28. Patients also receive high-dose MTX IV over 4 hours on day 1 in weeks 15, 19, 23,
27, 31, 35, 39, and 40. Patients receive ifosfamide IV over 4 hours on days 1-5 in weeks 16,
24, and 32 and on days 1-3 in weeks 20 and 36 and etoposide IV over 1 hour on days 1-5 in
weeks 16, 24, and 32.

In both groups, treatment continues in the absence of disease progression or unacceptable
toxicity. Quality of life is assessed periodically.

After completion of study treatment, patients are followed every 1½-3 months for 2 years,
every 2-4 months for 2 years, every 6 months for 6 years, and then every 6-12 months
thereafter. Peer Reviewed and Funded or Endorsed by Cancer Research UK

Inclusion Criteria:

- Histologically confirmed high-grade osteosarcoma, including second malignancies

- Localized or metastatic disease

- The primary tumor must be located in the limbs or axial skeleton, including any
of the following sites*:

- Long bone of upper limb

- Short bone of upper limb

- Long bone of lower limb

- Short bone of lower limb

- Vertebral column

- Ribs, sternum, clavicle, or scapula

- Pelvic bones, sacrum, or coccyx

- Tumor (primary, metastatic, or both) resectable OR is expected to become resectable
after neoadjuvant induction chemotherapy

- Suitable for neoadjuvant chemotherapy

- Performance status - Lansky 50-100% (for patients under 16 years of age)

- Performance status - Karnofsky 50-100%*

- Performance status - WHO or ECOG 0-2*

- Platelet count ≥ 100,000/mm³

- Neutrophil count ≥ 1,500/mm³

- WBC ≥ 3,000/mm³

- Bilirubin ≤ 1.5 times upper limit of normal

- Creatinine clearance ≥ 70 mL/min

- Creatinine based on age as follows:

- No greater than 1.0 mg/dL (for patients 5 to 10 years of age)

- No greater than 1.2 mg/dL (for patients 11 to 15 years of age)

- No greater than 1.5 mg/dL (for patients over 15 years of age)

- Ejection fraction ≥ 50% by radionuclide angiogram

- Shortening fraction ≥ 28% by echocardiogram

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No known HIV positivity

- No prior chemotherapy for any disease

- Prior radiotherapy for another malignancy allowed

- No prior treatment for osteosarcoma

Type of Study:


Study Design:

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

Outcome Measure:

Event-free survival

Outcome Description:

Will be assessed using the logrank test and expressed using hazard ratios with appropriate confidence intervals.

Outcome Time Frame:

From date of randomization to date of the event, assessed up to 10 years

Safety Issue:


Principal Investigator

Neyssa Marina

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group


United States: Institutional Review Board

Study ID:




Start Date:

November 2005

Completion Date:

Related Keywords:

  • Localized Osteosarcoma
  • Metastatic Osteosarcoma
  • Osteosarcoma



Baylor College of Medicine Houston, Texas  77030
Johns Hopkins University Baltimore, Maryland  21205
Cleveland Clinic Foundation Cleveland, Ohio  44195
Roswell Park Cancer Institute Buffalo, New York  14263
Mayo Clinic Rochester, Minnesota  55905
Children's Hospital of Philadelphia Philadelphia, Pennsylvania  19104
University of Iowa Hospitals and Clinics Iowa City, Iowa  52242
University of Mississippi Medical Center Jackson, Mississippi  39216-4505
Washington University School of Medicine Saint Louis, Missouri  63110
Medical University of South Carolina Charleston, South Carolina  29425-0721
Hurley Medical Center Flint, Michigan  48503
Medical City Dallas Hospital Dallas, Texas  75230
University of Texas Health Science Center at San Antonio San Antonio, Texas  78284-7811
Midwest Children's Cancer Center Milwaukee, Wisconsin  53226
Sinai Hospital of Baltimore Baltimore, Maryland  21225
Geisinger Medical Center Danville, Pennsylvania  17822-0001
Vanderbilt-Ingram Cancer Center Nashville, Tennessee  37232-6838
Massachusetts General Hospital Cancer Center Boston, Massachusetts  02114
Marshfield Clinic Marshfield, Wisconsin  54449
Loma Linda University Medical Center Loma Linda, California  92354
Baptist Hospital of Miami Miami, Florida  33176-2197
Newark Beth Israel Medical Center Newark, New Jersey  07112
New York Medical College Valhalla, New York  10595
Dana-Farber Cancer Institute Boston, Massachusetts  02115
Cedars-Sinai Medical Center Los Angeles, California  90048
University of Arkansas for Medical Sciences Little Rock, Arkansas  72205
Eastern Maine Medical Center Bangor, Maine  04401
William Beaumont Hospital Royal Oak, Michigan  48073
University of Nebraska Medical Center Omaha, Nebraska  68198-3330
Hackensack University Medical Center Hackensack, New Jersey  07601
Children's Hospital Los Angeles Los Angeles, California  90027-0700
Children's National Medical Center Washington, District of Columbia  20010-2970
All Children's Hospital St. Petersburg, Florida  33701
Advocate Hope Children's Hospital Oak Lawn, Illinois  60453
Saint Jude Midwest Affiliate Peoria, Illinois  61637
Maine Children's Cancer Program Scarborough, Maine  04074-9308
Carolinas Medical Center Charlotte, North Carolina  28232-2861
University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma  73104
Legacy Emanuel Hospital and Health Center Portland, Oregon  97227
Driscoll Children's Hospital Corpus Christi, Texas  78466
Scott and White Memorial Hospital Temple, Texas  76508
Inova Fairfax Hospital Falls Church, Virginia  22042-3300
Southern California Permanente Medical Group Downey, California  90242
Children's Hospital Central California Madera, California  93638-8762
Kosair Children's Hospital Louisville, Kentucky  40202-3830
Brooklyn Hospital Center Brooklyn, New York  11201
Children's Hospital Medical Center of Akron Akron, Ohio  44308
University of Wisconsin Hospital and Clinics Madison, Wisconsin  53792-0001
Overlook Hospital Summit, New Jersey  07902-0220
Mount Sinai Medical Center New York, New York  10029
Cincinnati Children's Hospital Medical Center Cincinnati, Ohio  45229-3039
Methodist Children's Hospital of South Texas San Antonio, Texas  78229-3993
Primary Children's Medical Center Salt Lake City, Utah  84113-1100
Montefiore Medical Center Bronx, New York  10467-2490
Saint Peter's University Hospital New Brunswick, New Jersey  08901-1780
Rady Children's Hospital - San Diego San Diego, California  92123-4282
Children's Hospitals and Clinics of Minnesota - Minneapolis Minneapolis, Minnesota  55404
University of New Mexico Cancer Center Albuquerque, New Mexico  87131-5636
Nationwide Children's Hospital Columbus, Ohio  43205-2696
Children's Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania  15213
Children's Hospital and Research Center at Oakland Oakland, California  94609-1809
Mary Bridge Children's Hospital and Health Center Tacoma, Washington  98415-0299
City of Hope Medical Center Duarte, California  91010
Presbyterian Hospital Charlotte, North Carolina  28233-3549
Lee Memorial Health System Fort Myers, Florida  33902
University of Virginia Charlottesville, Virginia  22908
University of Alabama at Birmingham Birmingham, Alabama  35294-3300
Connecticut Children's Medical Center Hartford, Connecticut  06106
University of North Carolina Chapel Hill, North Carolina  27599
Duke University Medical Center Durham, North Carolina  27710
University of Florida Gainesville, Florida  32610-0277
University of Rochester Rochester, New York  14642
Nemours Children's Clinic - Pensacola Pensacola, Florida  32504
Helen DeVos Children's Hospital at Spectrum Health Grand Rapids, Michigan  49503
Yale University New Haven, Connecticut  06520
Wayne State University Detroit, Michigan  48202
University of Arizona Health Sciences Center Tucson, Arizona  85724
University of Massachusetts Medical School Worcester, Massachusetts  01605
Indiana University Medical Center Indianapolis, Indiana  46202
University Of Vermont Burlington,, Vermont  05403
Albany Medical Center Albany, New York  12208
University of Texas Southwestern Medical Center Dallas, Texas  
University of Kentucky Lexington, Kentucky  40536-0098
UC Davis Comprehensive Cancer Center Sacramento, California  95817
Oregon Health and Science University Portland, Oregon  97201
Tulane University Health Sciences Center New Orleans, Louisiana  70112
Virginia Commonwealth University Richmond, Virginia  
David Geffen School of Medicine at UCLA Los Angeles, California  90095
Florida Hospital Orlando, Florida  32803
Memorial Health University Medical Center Savannah, Georgia  31404
M D Anderson Cancer Center Houston, Texas  77030
Seattle Children's Hospital Seattle, Washington  98105
Wake Forest University Health Sciences Winston-Salem, North Carolina  27157
Childrens Memorial Hospital Chicago, Illinois  60614
Kaiser Permanente-Oakland Oakland, California  94611
Lombardi Comprehensive Cancer Center at Georgetown University Washington, District of Columbia  20057
M D Anderson Cancer Center- Orlando Orlando, Florida  32806
University of Hawaii Honolulu, Hawaii  96813
Saint Vincent Hospital and Health Services Indianapolis, Indiana  46260
Michigan State University - Breslin Cancer Center East Lansing, Michigan  48824-1313
Kalamazoo Center for Medical Studies Kalamazoo, Michigan  49008
Nevada Cancer Research Foundation CCOP Las Vegas, Nevada  89106
New York University Langone Medical Center New York, New York  10016
Columbia University Medical Center New York, New York  10032
State University of New York Upstate Medical University Syracuse, New York  13210
Mission Hospitals Inc Asheville, North Carolina  28801
Saint Vincent Hospital Green Bay, Wisconsin  54301
University of Illinois Chicago, Illinois  60612
Cook Children's Medical Center Fort Worth, Texas  76104
Memorial Healthcare System - Joe DiMaggio Children's Hospital Hollywood, Florida  33021
East Carolina University Greenville, North Carolina  27858
The Children's Medical Center of Dayton Dayton, Ohio  45404
University of Miami Miller School of Medicine-Sylvester Cancer Center Miami, Florida  33136
University of Minnesota Medical Center-Fairview Minneapolis, Minnesota  55455
Children's Oncology Group Arcadia, California  91006-3776
C S Mott Children's Hospital Ann Arbor, Michigan  48109
Southern Illinois University Springfield, Illinois  62702
Cardinal Glennon Children's Medical Center St. Louis, Missouri  63104
UMDNJ - Robert Wood Johnson University Hospital New Brunswick, New Jersey  08903
Phoenix Childrens Hospital Phoenix, Arizona  85016
Miller Children's Hospital Long Beach, California  90806
Childrens Hospital of Orange County Orange, California  92868-3874
Alfred I duPont Hospital for Children Wilmington, Delaware  19803
Nemours Children's Clinic - Jacksonville Jacksonville, Florida  32207-8426
Nemours Childrens Clinic - Orlando Orlando, Florida  32806
Saint Joseph Children's Hospital of Tampa Tampa, Florida  33607
Children's Healthcare of Atlanta - Egleston Atlanta, Georgia  30322
The Childrens Mercy Hospital Kansas City, Missouri  64108
Rainbow Babies and Childrens Hospital Cleveland, Ohio  44106
Penn State Hershey Children's Hospital Hershey, Pennsylvania  17033
Palmetto Health Richland Columbia, South Carolina  29203
East Tennessee Childrens Hospital Knoxville, Tennessee  37916
Children's Hospital and Medical Center of Omaha Omaha, Nebraska  68114
Saint Joseph's Regional Medical Center Paterson, New Jersey  07503
Texas Tech University Health Science Center-Amarillo Amarillo, Texas  79106
Childrens Hospital-King's Daughters Norfolk, Virginia  23507
Sanford Medical Center-Fargo Fargo, North Dakota  58122
Children's Hospital Colorado Aurora, Colorado  80045
Lucile Packard Children's Hospital Stanford University Palo Alto, California  94304
University of California San Francisco Medical Center-Parnassus San Francisco, California  94143
Raymond Blank Children's Hospital Des Moines, Iowa  50309
Children's Hospital-Main Campus New Orleans, Louisiana  70118
Saint Christopher's Hospital for Children Philadelphia, Pennsylvania  19134
Greenville Cancer Treatment Center Greenville, South Carolina  29605
Sanford USD Medical Center - Sioux Falls Sioux Falls, South Dakota  57117-5134
T C Thompson Children's Hospital Chattanooga, Tennessee  37403
Carilion Clinic Children's Hospital Roanoke, Virginia  24014
Providence Sacred Heart Medical Center and Children's Hospital Spokane, Washington  99204
The Steven and Alexandra Cohen Children's Medical Center of New York New Hyde Park, New York  11040
Georgia Regents University Augusta, Georgia  30912