Surgery and/or Chemotherapy in Treating Children With Infantile, Congenital, or Childhood Fibrosarcoma

A Pilot Phase II Study for Children With Infantile Fibrosarcoma

RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Giving combination chemotherapy before surgery may shrink the tumor so that it can be removed. Giving combination chemotherapy after surgery may kill any remaining tumor cells.

PURPOSE: This phase II trial is studying how well surgery and/or combination chemotherapy work in treating children with fibrosarcoma.

Study Overview

• Status: Terminated
• Conditions: Sarcoma
• Intervention / Treatment: Biological: dactinomycin; Drug: cyclophosphamide; Drug: etoposide; Drug: ifosfamide; Drug: vincristine sulfate; Procedure: Conventional Surgery; Biological: MESNA (mercaptoethane sulfonate); Biological: Filgrastim

Detailed Description

OBJECTIVES:

Primary

• Determine the event-free and relapse-free survival of children with initially unresectable congenital, infantile, or childhood fibrosarcoma treated with neoadjuvant chemotherapy comprising vincristine, dactinomycin, and cyclophosphamide (VAC) before definitive local control.

Secondary

• Determine the event-free and relapse-free survival of patients initially treated with this regimen followed by observation after local control with positive microscopic margins.
• Determine the event-free and relapse-free survival of patients initially treated with this regimen followed by additional chemotherapy comprising etoposide and ifosfamide after local control with gross positive margins.
• Determine the event-free and relapse-free survival of patients treated with surgery alone.

OUTLINE: This is a pilot, multicenter study. Patients begin treatment according to lesion resectability.

Patients with resectable lesions proceed to surgery.

• Surgery: Patients undergo resection of disease lesions. Patients with clear or microscopically positive margins undergo observation only. Patients with grossly positive margins undergo re-resection if feasible. Patients with grossly positive margins after re-resection or for whom re-resection is not feasible receive chemotherapy comprising vincristine, dactinomycin, and cyclophosphamide (VAC).

Patients with unresectable lesions receive VAC chemotherapy.

• VAC chemotherapy: Patients receive vincristine intravenously (IV) on days 1, 8, and 15 and dactinomycin IV and cyclophosphamide IV over 1 hour on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Patients with disease progression after 2-4 courses of VAC chemotherapy proceed to chemotherapy comprising etoposide and ifosfamide (IE).

Patients with stable disease after 4 courses of VAC chemotherapy proceed to IE chemotherapy.

Patients with a partial response (PR) and unresectable lesions after 4 courses of VAC chemotherapy receive 2 additional courses of VAC and are then re-evaluated. Patients proceed to surgery if they continue to have a PR or achieve a complete response (CR) and lesions are now resectable.

Patients with a CR or PR and resectable lesions after 4 courses of VAC chemotherapy proceed to surgery.

Patients with stable disease, progressive disease, or a PR and unresectable lesions after 6 courses of VAC proceed to IE chemotherapy.

• IE chemotherapy: Patients receive etoposide IV over 1 hour and ifosfamide IV over 1 hour on days 1-5. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Patients with a CR or PR and resectable lesions after 2-4 courses of IE chemotherapy proceed to surgery.

All patients are followed every 3 months for 6 months, every 6 months for 1 year, and then as clinically indicated.

PROJECTED ACCRUAL: A total of 60-70 patients will be accrued for this study within 8 years.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Westmead Institute for Cancer Research at Westmead Hospital
  • South Australia
    • North Adelaide, South Australia, Australia, 5006
      • Women's and Children's Hospital
• Canada
  • Alberta
    • 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
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3K 6R8
      • IWK Health Centre
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H3H 1P3
      • Montreal Children's Hospital at McGill University Health Center
    • Montreal, Quebec, Canada, H3T 1C5
      • Hopital Sainte Justine
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 4H4
      • Saskatoon Cancer Centre at the University of Saskatchewan
• New Zealand
  • Auckland, New Zealand, 1
    • Starship Children's Health
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016-7710
      • Phoenix Children's Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
  • California
    • Downey, California, United States, 90242-2814
      • Southern California Permanente Medical Group
    • 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
    • Sacramento, California, United States, 95825
      • Kaiser Permanente Medical Center - Oakland
    • San Francisco, California, United States, 94115
      • UCSF Comprehensive Cancer Center
    • Stanford, California, United States, 94305
      • Stanford Comprehensive Cancer Center - Stanford
  • Connecticut
    • Farmington, Connecticut, United States, 06360-2875
      • Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Lombardi Comprehensive Cancer Center at Georgetown University Medical Center
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Lee Cancer Care of Lee Memorial Health System
    • Miami, Florida, United States, 33136
      • University Of Miami Sylvester Comprehensive Cancer Center
    • Pensacola, Florida, United States, 32504
      • Sacred Heart Cancer Center at Sacred Heart Hospital
    • St. Petersburg, Florida, United States, 33701
      • All Children's Hospital
    • Tampa, Florida, United States, 33607
      • St. Joseph's Cancer Institute at St. Joseph's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
    • Augusta, Georgia, United States, 30912-3730
      • MBCCOP - Medical College of Georgia Cancer Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5289
      • Indiana University Cancer Center
    • Indianapolis, Indiana, United States, 46260
      • St. Vincent Indianapolis Hospital
  • Kentucky
    • Louisville, Kentucky, United States, 40232
      • Kosair Children's Hospital
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Cancer Institute at Ochsner Clinic Foundation
  • Maine
    • Bangor, Maine, United States, 04401
      • CancerCare of Maine at Eastern Maine Medial Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
  • Michigan
    • Flint, Michigan, United States, 48503
      • Hurley Medical Center
    • Grand Rapids, Michigan, United States, 49503-2560
      • Spectrum Health Hospital - Butterworth Campus
    • Grosse Pointe Woods, Michigan, United States, 48236
      • Van Elslander Cancer Center at St. John Hospital and Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Medical Center & Children's Hospital - Fairview
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospitals and Clinics of Minneapolis
  • Mississippi
    • Jackson, Mississippi, United States, 39216-4505
      • University of Mississippi Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center Cancer Center
    • Morristown, New Jersey, United States, 07962
      • Overlook Hospital
  • New York
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center at Columbia University
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Hospital
  • North Carolina
    • 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
    • Durham, North Carolina, United States, 27710
      • Duke Comprehensive Cancer Center
  • Ohio
    • Akron, Ohio, United States, 44308-1062
      • Children's Hospital Medical Center of Akron
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106-5000
      • Rainbow Babies and Children's Hospital
    • Columbus, Ohio, United States, 43205-2696
      • Columbus Children's Hospital
    • Dayton, Ohio, United States, 45404-1815
      • Children's Medical Center - Dayton
    • Youngstown, Ohio, United States, 44501
      • Tod Children's Hospital - Forum Health
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • OU Cancer Institute
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822-0001
      • Geisinger Medical Center
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Cancer Institute at Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104-9786
      • Children's Hospital of Philadelphia
  • 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
    • Greenville, South Carolina, United States, 29605
      • Greenville Hospital System Cancer Center
  • Tennessee
    • Knoxville, Tennessee, United States, 37916
      • East Tennessee Children's Hospital
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
    • Nashville, Tennessee, United States, 37232-6310
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • 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
    • 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
  • Utah
    • Salt Lake City, Utah, United States, 84113-1100
      • Primary Children's Medical Center
  • Washington
    • Spokane, Washington, United States, 99220-2555
      • Providence Cancer Center at Sacred Heart Medical Center
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54307-3508
      • St. Vincent Hospital Regional Cancer Center
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic - Marshfield Center
    • Milwaukee, Wisconsin, United States, 53226
      • Midwest Children's Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 2 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed infantile, congenital, or pediatric fibrosarcoma

  • Initial biopsy or surgery performed within the past 35 days
• No evidence of distant metastases
• Available tissue for central review

PATIENT CHARACTERISTICS:

Age

• Under 2 at diagnosis

Performance status

• Zubrod Score (ECOG)

Life expectancy

• At least 8 weeks

Hematopoietic

• Absolute neutrophil count at least 1,000/mm^3
• Platelet count at least 100,000/mm^3*
• Hemoglobin at least 10.0 g/dL* NOTE: *Transfusions allowed

Hepatic

• Total bilirubin no greater than 1.5 times upper limit of normal (ULN) (patients over 4 weeks of age)

  • Patients under 4 weeks of age with an indirect hyperbilirubinemia are eligible, provided the following criteria are met:

    • At least 2 bilirubin values at separate timepoints show a decrease in measurement
    • Direct bilirubin is no greater than 20% of the total bilirubin
• Direct bilirubin no greater than 1.5 times ULN
• Alanine Aminotransferase (ALT) less than 2.5 times ULN

Renal

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

PRIOR/CONCURRENT THERAPY:

Biologic therapy

• No concurrent sargramostim (GM-CSF)

Chemotherapy

• No prior chemotherapy
• No other concurrent anticancer chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No prior or concurrent radiotherapy except emergent radiotherapy for impending tracheal compression

Surgery

• See Disease Characteristics

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Chemotherapy plus possible surgery; Comprised of patients with disease lesions that are initially unresectable, or resected but with resulting grossly positive margins. All patients receive vincristine sulfate, dactinomycin, and cyclophosphamide (VAC), and mercaptoethane sulfonate (MESNA). Depending on response, patients may receive ifosfamide and etoposide (IE). Filgrastim may also be given, as needed. In addition to Chemotherapy, patients may receive Conventional Surgery. (See Interventions section for drug dosage and administration details.)	Biological: dactinomycin; Given Slow intravenous (IV) push over 1-5 minutes, dose < 1yr 0.025 mg/kg > or = 1 yr 0.045 mg/kg (max dose 2.5 mg) on days 1,22,43 and 64; Other Names: Cosmegen; DACT; Actinomycin-D; NSC #3053; Drug: cyclophosphamide; Given IV over 60 minutes, dose 25 mg/kg on days 1,22,43 and 64.; Other Names: Cytoxan; NSC #26271; Drug: etoposide; Given IV over 1 hour, dose 3.3 mg/kg in normal saline (NS) 10 cc/kg (or to equal 0.4 mg/mL concentration) on days 1-5 of IE cycle.; Other Names: VP-16; Etopophos; VePesid; NSC #141540; ETOP; Drug: ifosfamide; Given IV over 1 hour, dose 60mg/kg in D5 1/4 NS 10 cc/kg IV on days 1-5 of IE Cycle; Other Names: Ifex; Iphosphamide; Isophosphamide; Z4942; NSC #109724; Drug: vincristine sulfate; Given IV Push over 1 minute, dose 0.05 mg/kg (max dose 2 mg) on days 1,8,15,22,29,36,43,50,57 and 64; Other Names: VCR; Oncovin; LCR; NSC #67574; Procedure: Conventional Surgery; Applied only when lesion is resectable. Surgery is the primary means of local control in this study and reasonable attempts at achieving clear margins with an "envelope" of normal tissue should be undertaken at the initial and/or subsequent resections.; Biological: MESNA (mercaptoethane sulfonate); Given orally. Oral daily MESNA dose is equal to at least 60% of the daily cyclophosphamide dose.; Other Names: Mesnex; UCB 3983; NSC #113891; Sodium 2-mercaptoethane sulfonate; Biological: Filgrastim; Given IV - Only use filgrastim if chemotherapy has been delayed or modified for hematologic toxicity, or if patient experiences a significant life-threatening toxicity due to bone marrow suppression; Other Names: G-CSF; Granulocyte Colony-Stimulating Factor; r-metHuG-CSF; Neupogen; NSC #614629
EXPERIMENTAL: Surgery only; Comprised of patients with initially resectable disease lesions. All patients undergo Conventional Surgery. Those with a result of clear or microscopically positive margins remain on study in this arm, for observation with no further intervention.	Procedure: Conventional Surgery; Applied only when lesion is resectable. Surgery is the primary means of local control in this study and reasonable attempts at achieving clear margins with an "envelope" of normal tissue should be undertaken at the initial and/or subsequent resections.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Failure-free Survival (FFS) in "Chemotherapy Plus Possible Surgery" Arm	Failure is defined as the occurrence of one of the following: disease progression, defined as at least a 20% increase in the disease measurement, taking as reference the smallest disease measurement recorded since the start of treatment, or the appearance of one or more new lesions; relapse (defined with same criteria as for disease progression) after response; or death as a first event. Data will be summarized as number of eligible patients in each of the following categories at the time of data cutoff for analyses of 5-year FFS: 1)Failed; 2)Failure-free through 5 years of follow-up; 3)Failure-free until data cutoff (if less than 5 years of follow-up); 4)Withdrew from study; 5)Lost to follow-up. NOTE: Reported data are through March 2008 (see Caveats section).	Study enrollment until failure, completion of follow-up, or completion of 5-year FFS analyses (up to 5 years)

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Anne B. Warwick, MD, MPH, Medical College of Wisconsin

Study record dates

Study Major Dates

• Study Start: November 1, 2004
• Primary Completion (ACTUAL): March 1, 2008
• Study Completion (ACTUAL): March 1, 2008

Study Registration Dates

• First Submitted: November 4, 2003
• First Submitted That Met QC Criteria: November 5, 2003
• First Posted (ESTIMATE): November 6, 2003

Study Record Updates

• Last Update Posted (ESTIMATE): September 30, 2014
• Last Update Submitted That Met QC Criteria: September 16, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: nonmetastatic childhood soft tissue sarcoma; childhood fibrosarcoma
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Connective Tissue; Neoplasms, Fibrous Tissue; Sarcoma; Fibrosarcoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Adjuvants, Immunologic; Protein Synthesis Inhibitors; Antibiotics, Antineoplastic; Cyclophosphamide; Etoposide; Ifosfamide; Isophosphamide mustard; Lenograstim; Vincristine; Dactinomycin; Mesna
• Other Study ID Numbers: ARST03P1; CDR0000339565 (OTHER: PDQ (Physician Data Query)); NCI-2012-02561 (OTHER: NCI); COG-ARST03P1 (OTHER: Children's Oncology Group)