Surgery and Combination Chemotherapy in Treating Children With Extracranial Germ Cell Tumors

A Phase III Study Of Reduced Therapy In The Treatment Of Children With Low And Intermediate Risk Extracranial Germ Cell Tumors

This phase III trial is studying surgery followed by combination chemotherapy to see how well it works in treating children with germ cell tumors that are not located in the head. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug, and giving them after surgery, may kill any remaining tumor cells following surgery. It is not yet known whether combination chemotherapy is effective in decreasing the recurrence of childhood germ cell tumors.

Study Overview

• Status: Completed
• Conditions: Childhood Teratoma; Stage II Malignant Testicular Germ Cell Tumor; Stage III Malignant Testicular Germ Cell Tumor; Childhood Embryonal Tumor; Childhood Extracranial Germ Cell Tumor; Childhood Extragonadal Germ Cell Tumor; Childhood Malignant Ovarian Germ Cell Tumor; Childhood Malignant Testicular Germ Cell Tumor; Ovarian Embryonal Carcinoma; Ovarian Yolk Sac Tumor; Stage IIA Ovarian Germ Cell Tumor; Stage IIB Ovarian Germ Cell Tumor; Stage IIC Ovarian Germ Cell Tumor; Stage IIIA Ovarian Germ Cell Tumor; Stage IIIB Ovarian Germ Cell Tumor; Stage IIIC Ovarian Germ Cell Tumor; Testicular Choriocarcinoma and Yolk Sac Tumor; Testicular Embryonal Carcinoma
• Intervention / Treatment: Other: laboratory biomarker analysis; Procedure: conventional surgery; Drug: etoposide; Drug: cisplatin; Biological: bleomycin sulfate

Detailed Description

OBJECTIVES:

I. Determine whether children with newly diagnosed low- or intermediate-risk extracranial germ cell tumors (GCTs) can maintain a 3-year event-free survival of at least 92% (for intermediate-risk tumors only) and overall survival of at least 95% (both low-risk and intermediate-risk tumors) after treatment with surgery followed by compressed cisplatin, etoposide, and bleomycin (low-risk disease closed to accrual as of 01/20/10).

II. Determine the percentage of patients with stage I ovarian or stage I testicular GCTs for whom chemotherapy can be eliminated.

III. Determine the percentage of intermediate-risk patients who require only 3 courses of therapy.

IV. Determine the acute toxic effects of compressed therapy in these patients. V. Determine the long-term sequelae in patients treated with this regimen. VI. Determine the number of hospital days and total drug doses required for patients treated with compressed therapy.

VII. Compare the number of protocol-directed treatment days used in CCG-8882 vs the number of treatment days used in this study.

VIII. Determine the cytogenetic and molecular genetic features in patients treated with this regimen.

OUTLINE: Patients are stratified according to disease risk (low vs intermediate).

SURGERY: Patients undergo surgical resection.

Low-risk disease: Patients with gonadal primaries and no evidence of disease after surgery undergo monitoring for disease progression. Patients who remain disease free receive no further treatment. Patients who have disease progression after surgery receive compressed induction chemotherapy. (closed to accrual as of 01/20/2010)

Intermediate-risk disease: After surgery, patients proceed to compressed induction chemotherapy.

COMPRESSED INDUCTION CHEMOTHERAPY: Patients receive cisplatin IV over 90 minutes and etoposide IV over 90 minutes on days 1-3 and bleomycin IV over ≥ 10 minutes on day 1. Treatment repeats every 3 weeks for 3 courses (weeks 0, 3, and 6).

After completion of compressed induction chemotherapy, patients who have no change in disease status or disease progression are removed from study. Patients with no evidence of disease receive no further therapy. Patients with a partial response or who have abnormal tumor markers proceed to second-look surgery and/or 3 more courses of compressed consolidation chemotherapy.

SECOND-LOOK SURGERY: Patients undergo surgical resection of residual tumor. After surgery, patients who are in pathologic complete response and have normal tumor markers receive no further therapy. Patients who remain with a partial response after surgery receive compressed consolidation chemotherapy.

COMPRESSED CONSOLIDATION CHEMOTHERAPY: Patients receive cisplatin, etoposide, and bleomycin as in induction chemotherapy in weeks 10, 13, and 16.

Patients are followed up monthly for 6 months, every 3 months for 18 months, and then annually for up to 10 years.

• Study Type: Interventional
• Enrollment (Actual): 302
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2145
      • The Children's Hospital at Westmead
  • Western Australia
    • Perth, Western Australia, Australia, 6008
      • Princess Margaret Hospital for Children
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Alberta Children's Hospital
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • British Columbia Children's Hospital
  • Ontario
    • Hamilton, Ontario, Canada, L8S 4L8
      • Chedoke-McMaster Hospitals
    • Kingston, Ontario, Canada, K7L 5P9
      • Cancer Centre of Southeastern Ontario at Kingston General Hospital
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Hospital Sainte-Justine
    • Ste-Foy, Quebec, Canada, G1V 4G2
      • Centre Hospitalier Universitaire de Québec
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4T 7T1
      • Allan Blair Cancer Centre
• New Zealand
  • Auckland
    • Grafton, Auckland, New Zealand, 1145
      • Starship Children's Hospital
• Puerto Rico
  • Santurce, Puerto Rico, 00912
    • San Jorge Children's Hospital
• Switzerland
  • Geneva, Switzerland, 1205
    • Swiss Pediatric Oncology Group - Geneva
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Childrens Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • Downey, California, United States, 90242
      • Southern California Permanente Medical Group
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
    • Long Beach, California, United States, 90806
      • Miller Children's Hospital
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Madera, California, United States, 93636-8762
      • Children's Hospital Central California
    • Oakland, California, United States, 94611
      • Kaiser Permanente-Oakland
    • Oakland, California, United States, 94609-1809
      • Children's Hospital and Research Center at Oakland
    • Orange, California, United States, 92868-3874
      • Childrens Hospital of Orange County
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital Stanford University
    • Sacramento, California, United States, 95816
      • Sutter General Hospital
    • San Diego, California, United States, 92123
      • Rady Children's Hospital - San Diego
    • San Francisco, California, United States, 94143
      • University of California San Francisco Medical Center-Parnassus
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center
    • New Haven, Connecticut, United States, 06520-8032
      • Yale University
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfred I duPont Hospital for Children
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Fort Lauderdale, Florida, United States, 33316
      • Broward Health Medical Center
    • Fort Myers, Florida, United States, 33901
      • Lee Memorial Health System
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Hollywood, Florida, United States, 33021
      • Memorial Healthcare System - Joe DiMaggio Children's Hospital
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine-Sylvester Cancer Center
    • Miami, Florida, United States, 33155
      • Miami Children's Hospital
    • Saint Petersburg, Florida, United States, 33701
      • All Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta - Egleston
    • Savannah, Georgia, United States, 31403
      • Memorial Health University Medical Center
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • University of Hawaii
  • Idaho
    • Boise, Idaho, United States, 83712
      • Saint Luke's Mountain States Tumor Institute
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Childrens Memorial Hospital
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
    • Oak Lawn, Illinois, United States, 60453
      • Advocate Hope Children's Hospital
    • Peoria, Illinois, United States, 61602
      • Saint Jude Midwest Affiliate
    • Springfield, Illinois, United States, 62702
      • Southern Illinois University
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky
    • Louisville, Kentucky, United States, 40202
      • Kosair Children's Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
    • Springfield, Massachusetts, United States, 01199
      • Baystate Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • C S Mott Children's Hospital
    • Detroit, Michigan, United States, 48236
      • Saint John Hospital and Medical Center
    • Detroit, Michigan, United States, 48202
      • Wayne State University
    • Flint, Michigan, United States, 48502
      • Hurley Medical Center
    • Grand Rapids, Michigan, United States, 49503
      • Helen DeVos Children's Hospital at Spectrum Health
    • Lansing, Michigan, United States, 48910
      • Michigan State University - Breslin Cancer Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospitals and Clinics of Minnesota - Minneapolis
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Medical Center-Fairview
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • The Childrens Mercy Hospital
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
    • New Brunswick, New Jersey, United States, 08901
      • Saint Peter's University Hospital
    • New Brunswick, New Jersey, United States, 08903
      • UMDNJ - Robert Wood Johnson University Hospital
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical Center
    • Bronx, New York, United States, 10467-2490
      • Montefiore Medical Center
    • Brooklyn, New York, United States, 11201
      • Brooklyn Hospital Center
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New Hyde Park, New York, United States, 11040
      • The Steven and Alexandra Cohen Children's Medical Center of New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10016
      • New York University Langone Medical Center
    • Rochester, New York, United States, 14642
      • University of Rochester
    • Syracuse, New York, United States, 13210
      • State University of New York Upstate Medical University
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Mission Hospitals Inc
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • North Dakota
    • Fargo, North Dakota, United States, 58122
      • Sanford Medical Center-Fargo
  • Ohio
    • Akron, Ohio, United States, 44308
      • Children's Hospital Medical Center of Akron
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies and Childrens Hospital
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
    • Dayton, Ohio, United States, 45404
      • The Children's Medical Center of Dayton
    • Toledo, Ohio, United States, 43608
      • Mercy Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Hospital and Health Center
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822-2001
      • Geisinger Medical Center
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Children's Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Philadelphia, Pennsylvania, United States, 19134
      • Saint Christopher's Hospital for Children
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Columbia, South Carolina, United States, 29203
      • Palmetto Health Richland
  • Tennessee
    • Chattanooga, Tennessee, United States, 37403
      • T C Thompson Children's Hospital
    • Knoxville, Tennessee, United States, 37916
      • East Tennessee Childrens Hospital
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • Amarillo, Texas, United States, 79106
      • Texas Tech University Health Science Center-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, 75390
      • University of Texas Southwestern Medical Center
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Lubbock, Texas, United States, 79410
      • Covenant Children's Hospital
    • San Antonio, Texas, United States, 78229
      • Methodist Children's Hospital of South Texas
    • San Antonio, Texas, United States, 78229-3900
      • University of Texas Health Science Center at San Antonio
    • Temple, Texas, United States, 76508
      • Scott and White Memorial Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Medical Center
  • Vermont
    • Burlington, Vermont, United States, 05401
      • University of Vermont
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Childrens Hospital-King's Daughters
    • Roanoke, Virginia, United States, 24014
      • Carilion Clinic Children's Hospital
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
  • West Virginia
    • Charleston, West Virginia, United States, 25304
      • West Virginia University Charleston
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54301
      • Saint Vincent Hospital
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic
    • Milwaukee, Wisconsin, United States, 53226
      • Midwest Children's Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Extracranial germ cell tumor that contains 1 of the following malignant histologies: NOTE: Mixed germ cell tumors that include mature/immature teratoma are eligible provided 1 of the 3 histologies listed above is also present in the tumor.

  • Yolk sac tumor
  • Embryonal carcinoma
  • Choriocarcinoma

• Low-risk disease (closed to accrual as of 01/20/10)

  • Stage I gonadal tumors (ovarian and testicular)
  • Must have undergone complete surgical and radiologic staging to exclude the possibility of > stage I disease

• Intermediate-risk disease

  • Stage II, III, or IV malignant testicular GCT
  • Stage II or III malignant ovarian GCT
  • Stage I or II malignant extragonadal GCT
  • Previously stage I gonadal patients who have relapsed on the low-risk (observation) stratum of this study(closed to accrual as of 01/20/10)
  • Patients with immature teratoma or mature teratoma who relapse with a malignant component

• No patients with any of the following diagnoses:

  • Stage IV ovarian and stage III-IV extragonadal GCT
  • Intracranial GCT
  • Pure mature or immature teratoma, pure dysgerminoma, or seminoma
  • Patients with a non-germ cell component in their GCT (e.g., primitive neuroectodermal tumors or rhabdomyosarcoma)

• Alpha-fetoprotein and beta human chorionic gonadotropin tumor markers known

  • If > 5 days have elapsed from the time of obtaining original markers, tumor markers must be repeated before enrollment of low-risk patients and before initiating therapy in intermediate-risk patients (the results of the repeated tumor markers do not have to be known at the time of study enrollment)
• Must be enrolled within 6 weeks of original diagnostic surgery

• Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR a serum creatinine based on age/gender as follows:

  • ≤ 0.4 mg/dL (for patients 1 to 5 months of age)
  • ≤ 0.5 mg/dL (for patients 6 to 11 months of age)
  • ≤ 0.6 mg/dL (for patients 1 year of age)
  • ≤ 0.8 mg/dL (for patients 2 to 5 years of age)
  • ≤ 1.0 mg/dL (for patients 6 to 9 years of age)
  • ≤ 1.2 mg/dL (for patients 10 to 12 years of age)
  • ≤ 1.4 mg/dL (for female patients ≥ 13 years of age)
  • ≤ 1.5 mg/dL (for male patients 13 to 15 years of age)
  • ≤ 1.7 mg/dL (for male patients ≥ 16 years of age)
• No prior chemotherapy
• No prior radiotherapy

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: Arm I; Patients enrolled with gonadal tumors of stage II or greater or extragonadal tumors of any stage receive cisplatin IV over 90 minutes & etoposide IV over 90 minutes days 1-3 and bleomycin sulfate IV over ≥ 10 minutes day 1. Treatment repeats every 3 weeks, 3 courses (weeks 0,3 & 6). After completion of compressed induction chemotherapy, patients with no change in disease status or disease progression are removed from study. Patients with no evidence of disease receive no further therapy. Patients with a partial response or abnormal tumor markers proceed to conventional surgery (second-look) and/or 3 more courses of compressed consolidation chemotherapy. After surgery, patients with pathologic complete response and have normal tumor markers receive no further therapy. Patients who remain with a partial response after surgery receive compressed consolidation chemotherapy. Patients receive cisplatin, etoposide, and bleomycin as induction chemotherapy in weeks 10,13, & 16.	Other: laboratory biomarker analysis; Correlative studies; Procedure: conventional surgery; Other Names: surgery, conventional; Drug: etoposide; Given IV; Other Names: EPEG; VP-16; VP-16-213; Drug: cisplatin; Given IV; Other Names: CDDP; DDP; CACP; CPDD; Biological: bleomycin sulfate; Given IV; Other Names: BLM; Blenoxane; BLEO
No Intervention: Arm 2; Patients who are enrolled with stage I gonadal tumors receive no further anticancer therapy until evidence of tumor recurrence or the diagnosis of a second malignant neoplasm. Observation only for recurrence or development of an SMN

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-Free Survival (EFS)	Proportion of patients event free at 3 years following enrollment. Event-free survival is not a primary outcome measure for Arm 2 patients.	3 Years after enrollment
Overall Survival (OS)	Percentage probability of being alive at 3 years following enrollment.	3 Years after enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days Hospitalized for Patients Who Receive Chemotherapy	Calculated to quantify the treatment cost associated with this regimen.	Up to 126 days after the start of chemotherapy
Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0	The number of patients assigned to receive chemotherapy that experience CTC Version 4 grade 3 or higher at any time during protocol therapy	Up to 126 days after the start of chemotherapy

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Anne Frazier, MD, Children's Oncology Group

Publications and helpful links

General Publications

• O'Neill AF, Xia C, Krailo MD, Shaikh F, Pashankar FD, Billmire DF, Olson TA, Amatruda JF, Villaluna D, Huang L, Malogolowkin M, Rodriguez-Galindo C, Frazier AL. alpha-Fetoprotein as a predictor of outcome for children with germ cell tumors: A report from the Malignant Germ Cell International Consortium. Cancer. 2019 Oct 15;125(20):3649-3656. doi: 10.1002/cncr.32363. Epub 2019 Jul 29.

Helpful Links

• Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive

Study record dates

Study Major Dates

• Study Start (Actual): November 3, 2003
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): June 30, 2021

Study Registration Dates

• First Submitted: January 27, 2003
• First Submitted That Met QC Criteria: January 27, 2003
• First Posted (Estimate): January 28, 2003

Study Record Updates

• Last Update Posted (Actual): July 13, 2021
• Last Update Submitted That Met QC Criteria: July 9, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Urogenital Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Genital Neoplasms, Male; Testicular Diseases; Pregnancy Complications; Pregnancy Complications, Neoplastic; Trophoblastic Neoplasms; Mesonephroma; Neoplasms; Neoplasms, Germ Cell and Embryonal; Testicular Neoplasms; Carcinoma; Ovarian Neoplasms; Teratoma; Choriocarcinoma; Endodermal Sinus Tumor; Germinoma; Carcinoma, Embryonal; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Etoposide; Etoposide phosphate; Bleomycin
• Other Study ID Numbers: AGCT0132; U10CA098543 (U.S. NIH Grant/Contract); NCI-2009-00373 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); CDR0000269433 (Other Identifier: Clinical Trials.gov); COG-AGCT0132 (Other Identifier: Children's Oncology Group)