Chemotherapy Followed by Radiation Therapy in Treating Young Patients With Newly Diagnosed Hodgkin's Disease

RESPONSE DEPENDENT TREATMENT OF STAGES IA, IIA AND IIIA HODGKIN'S DISEASE WITH DBVE AND LOW DOSE INVOLVED FIELD IRRADIATION WITH OR WITHOUT ZINECARD: A PEDIATRIC ONCOLOGY GROUP PHASE III STUDY

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage cancer cells. Combining chemotherapy with radiation therapy may kill more cancer cells. It is not yet known if chemotherapy is more effective with or without dexrazoxane for Hodgkin's disease.

PURPOSE: Randomized phase III trial to compare the effectiveness of combination chemotherapy, with or without dexrazoxane, followed by radiation therapy in treating young patients with newly diagnosed stage I, stage II, or stage III Hodgkin's disease.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Cardiac Toxicity
• Intervention / Treatment: Drug: etoposide; Drug: doxorubicin hydrochloride; Drug: vincristine sulfate; Drug: dexrazoxane hydrochloride; Radiation: low-LET electron therapy; Radiation: low-LET photon therapy; Biological: bleomycin sulfate; Biological: filgrastim; Radiation: low-LET cobalt-60 gamma ray therapy

Detailed Description

OBJECTIVES: I. Modify chemotherapy courses based on initial response to therapy in children with newly diagnosed stage IA/IIA/IIIA1 Hodgkin's disease. II. Examine the activity of variable courses of doxorubicin, bleomycin, vincristine, and etoposide (DBVE) followed by low-dose involved-field irradiation in these patients. III. Monitor the safety and feasibility of the response-dependent approach and the morbidity and immediate and long-term toxic effects associated with this regimen. IV. Assess whether limited therapy is adequate for patients with an early response. V. Evaluate whether the addition of dexrazoxane can reduce pulmonary toxicity while not significantly reducing the response rate or event-free survival. VI. Evaluate whether the frequency and magnitude of myocardial injury during therapy, as measured by elevated serum cardiac troponin-T, is reduced by the addition of dexrazoxane.

OUTLINE: This is a randomized study. Patients are stratified by participating institution. Patients are randomly assigned to receive doxorubicin, bleomycin, vincristine, etoposide, and filgrastim with vs. without dexrazoxane. Filgrastim SC begins on days 6-13; no filgrastim is given on day 14 or 15. Filgrastim will restart 2 days after completing therapy and continue until count recovery from expected nadir (ANC greater than 1000 cubic meter after nadir). Courses repeat every 28 days. Those with stable or responding disease after 2-4 courses receive involved-field radiotherapy 5 days per week for 3.5 weeks. Tanner stage IV/V patients are eligible for randomization based on a front-end institutional agreement and may receive standard-field radiotherapy 5 days per week for up to 11 weeks at the investigator's discretion. Patients are followed yearly until relapse, death, or for a minimum of 10 years.

PROJECTED ACCRUAL: A total of 285 patients will be accrued for this study over 5 years.

• Study Type: Interventional
• Enrollment (Actual): 294
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Western Australia
    • Perth, Western Australia, Australia, 6001
      • Princess Margaret Hospital for Children
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • British Columbia Children's Hospital
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3J 3G9
      • IWK Grace Health Centre
• United States
  • California
    • Long Beach, California, United States, 90806
      • Long Beach Memorial Medical Center
    • Los Angeles, California, United States, 90095-1781
      • Jonsson Comprehensive Cancer Center, UCLA
    • Los Angeles, California, United States, 90027-0700
      • Children's Hospital Los Angeles
    • Orange, California, United States, 92668
      • Children's Hospital of Orange County
    • San Francisco, California, United States, 94115-0128
      • UCSF Cancer Center and Cancer Research Institute
    • Travis Air Force Base, California, United States, 94535
      • David Grant Medical Center
  • Colorado
    • Denver, Colorado, United States, 80218
      • Children's Hospital of Denver
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-2970
      • Children's National Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Cancer Research Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5265
      • Indiana University Cancer Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0752
      • University of Michigan Comprehensive Cancer Center
    • Kalamazoo, Michigan, United States, 49007-3731
      • CCOP - Kalamazoo
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Cancer Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital - Kansas City
  • Nebraska
    • Omaha, Nebraska, United States, 68198-3330
      • University of Nebraska Medical Center
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Cancer Institute Of New Jersey
  • New York
    • New York, New York, United States, 10021
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10016
      • Kaplan Cancer Center
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7295
      • Lineberger Comprehensive Cancer Center, UNC
  • North Dakota
    • Fargo, North Dakota, United States, 58102
      • Veterans Affairs Medical Center - Fargo
    • Fargo, North Dakota, United States, 58122
      • CCOP - Merit Care Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Children's Hospital Medical Center - Cincinnati
    • Cleveland, Ohio, United States, 44106-5065
      • Ireland Cancer Center
    • Columbus, Ohio, United States, 43205-2696
      • Children's Hospital of Columbus
  • Oregon
    • Portland, Oregon, United States, 97201-3098
      • Doernbecher Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh
  • Tennessee
    • Nashville, Tennessee, United States, 37232-6838
      • Vanderbilt Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas - MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Huntsman Cancer Institute
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center - Seattle
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Comprehensive 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

DISEASE CHARACTERISTICS: Histologically proven Hodgkin's disease No more than 5 weeks since diagnostic biopsy No B symptoms Clinical/pathologic stages (all histologies) as follows: Stage IA/IIA with mediastinal mass less than one third of chest diameter Stage IIIA limited to spleen or splenic, celiac, or portal nodes and lesions no larger than 6 cm Surgical staging required if: Clinical and imaging findings equivocal Tanner stage IV/V for whom radiotherapy is planned Concurrent registration on protocols POG-8828 (late effects study) and POG- 8829 (epidemiology study) required

PATIENT CHARACTERISTICS: Age: 21 and under Performance status: Not specified Hematopoietic: No hematopoietic disease Hepatic: No liver disease Renal: No renal disease Other: No severe organ or system damage or failure No pregnant or nursing women

PRIOR CONCURRENT THERAPY: No prior therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment #1 (Without Zinecard); All patients undergoing a splenectomy must receive penicillin or erythromycin prophylaxis twice a day. Pneumocystis prophylaxis:TMP/SMZ 150mg/m2(maximum 300 mg) of TMP in 2 divided doses on 3 consecutive days each week. Aerosolized Pentamidine (200mg/m2/dose - maximum dose 300 mg) should be substituted monthly for patients who cannot tolerate TMP/SMZ therapy. Continue pneumocystis prophylaxis for 6 months after stopping therapy. Doxorubicin hydrochloride 25mg/m2/day IV push over 15 minutes days 1 and 15 Bleomycin sulfate 10 IU/m2/day IV push over 10 minutes on days 1 and 15 Vincristine sulfate 1.5mg/m2/day IV push (maximum 2mg) days 1 and 15 Etoposide 10mg/m2/day 1-5. IV drip ( < 0.4mg/ml) over 1 hour. Monitor blood pressure every 15 minutes during infusion. G-CSF (filgrastim) 5 mcg/Kg/day start on day 6 (24-36 hrs after 5th dose of VP16) and continued through day 13 (total 8 days).	Drug: etoposide; Given IV; Other Names: VP-16; VePesid; NSC #141540; Drug: doxorubicin hydrochloride; Given IV; Other Names: NSC #123127; Drug: vincristine sulfate; Given IV; Other Names: VCR; Oncovin; NSC #67574; Radiation: low-LET electron therapy; Radiation: low-LET photon therapy; Biological: bleomycin sulfate; Given IV; Other Names: Blenoxane; NSC #125066; Biological: filgrastim; Given IV; Other Names: G-CSF; r-metHuG-CSF; Neupogen; NSC #614629; Granulocyte-colony stimulating factor; Radiation: low-LET cobalt-60 gamma ray therapy
Experimental: Treatment #2 (with Zinecard); Zinecard (DZR) 250 mg/m2 IV push on days 1 and 15 before administration of doxorubicin and bleomycin sulfate. Give bleomycin sulfate and doxorubicin within 30 minutes of Zinecard (dexrazoxane hydrochloride). Bleomycin 10 IU/m2/day IV push over 10 minutes on days 1 and 15 Doxorubicin hydrochloride 25mg/m2/day IV push over 15 minutes days 1 and 15 Vincristine Sulfate 1.5mg/m2/day IV push (maximum 2mg) days 1 and 15	Drug: etoposide; Given IV; Other Names: VP-16; VePesid; NSC #141540; Drug: doxorubicin hydrochloride; Given IV; Other Names: NSC #123127; Drug: vincristine sulfate; Given IV; Other Names: VCR; Oncovin; NSC #67574; Drug: dexrazoxane hydrochloride; Given IV; Other Names: ADR-529; ICRF-187; DZR; ZINECARD; NSC #169780; Radiation: low-LET electron therapy; Radiation: low-LET photon therapy; Biological: bleomycin sulfate; Given IV; Other Names: Blenoxane; NSC #125066; Biological: filgrastim; Given IV; Other Names: G-CSF; r-metHuG-CSF; Neupogen; NSC #614629; Granulocyte-colony stimulating factor; Radiation: low-LET cobalt-60 gamma ray therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DLCO	The Wilcoxon test will be used to evaluate whether DLCO values differ between the two arms.	1 year post therapy

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI); Children's Cancer Group
• Investigators: Study Chair: Cameron K. Tebbi, MD, St. Joseph's Children's Hospital of Tampa; Study Chair: Michael A. Weiner, MD, Herbert Irving Comprehensive Cancer Center

Publications and helpful links

General Publications

• Tebbi CK, London WB, Friedman D, Villaluna D, De Alarcon PA, Constine LS, Mendenhall NP, Sposto R, Chauvenet A, Schwartz CL. Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol. 2007 Feb 10;25(5):493-500. doi: 10.1200/JCO.2005.02.3879.
• Schwartz CL, Tebbi CK, Constine LS: Response based therapy for pediatric Hodgkin's disease (HD): Pediatric Oncology Group (POG) protocols 9425/9426. [Abstract] Med Pediatr Oncol 37 (3): A-P219, 263, 2001.
• Tebbi CK, Mendenhall NP, London WB, Williams JL, Hutchison RE, Fitzgerald TJ, de Alarcon PA, Schwartz C, Chauvenet A. Response-dependent and reduced treatment in lower risk Hodgkin lymphoma in children and adolescents, results of P9426: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2012 Dec 15;59(7):1259-65. doi: 10.1002/pbc.24279. Epub 2012 Aug 21.
• Mendenhall NP, Meyer J, Williams J, et al.: The impact of central quality assurance review prior to radiation therapy on protocol compliance: POG 9426, a trial in pediatric Hodgkin's disease. [Abstract] Blood 106 (11): A-753, 2005.

Study record dates

Study Major Dates

• Study Start: October 1, 1996
• Primary Completion (Actual): October 1, 2004
• Study Completion (Actual): June 1, 2008

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: May 25, 2004
• First Posted (Estimate): May 26, 2004

Study Record Updates

• Last Update Posted (Estimate): August 26, 2013
• Last Update Submitted That Met QC Criteria: August 22, 2013
• Last Verified: August 1, 2013

More Information

Terms related to this study

• Keywords: stage III childhood Hodgkin lymphoma; stage I childhood Hodgkin lymphoma; stage II childhood Hodgkin lymphoma; cardiac toxicity
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Wounds and Injuries; Drug-Related Side Effects and Adverse Reactions; Radiation Injuries; Lymphoma; Hodgkin Disease; Cardiotoxicity; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protective Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Cardiotonic Agents; Trace Elements; Micronutrients; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Etoposide; Lenograstim; Doxorubicin; Liposomal doxorubicin; Vincristine; Bleomycin; Cobalt; Dexrazoxane; Razoxane
• Other Study ID Numbers: 9426 (Other Identifier: CTEP); POG-9426 (Other Identifier: Pediatric Oncology Group); CCG-P9426 (Other Identifier: Children's Cancer Group); CDR0000065013 (Other Identifier: Clinical Trials.gov); COG-9426 (Other Identifier: Children's Oncology Group)