Combination Chemotherapy in Treating Pediatric Patients With Advanced-Stage Large Cell Lymphoma

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Giving the drugs in different doses may kill more cancer cells. PURPOSE: Randomized phase III trial to compare the effectiveness of chemotherapy with various combinations of drugs in treating pediatric patients with advanced-stage large cell lymphoma.

Detailed Description
-----------------
OBJECTIVES: I. Compare the event free survival of children with advanced stage large cell lymphoma treated with modified APO (doxorubicin/prednisone/vincristine/mercaptopurine) with or without intermediate-dose methotrexate/high dose cytarabine as maintenance therapy following induction therapy with APO. II. Characterize further the immunophenotypic and morphologic correlates of pediatric large cell lymphoma. OUTLINE: This is a randomized, multicenter study. Patients are randomized to one of two treatment arms, except for those with CNS disease. These patients are assigned to arm II and receive whole brain irradiation on Regimen B. Arm I: Induction (Modified APO): Patients receive vincristine IV on days 1, 8, 15, 22, and 29, doxorubicin IV over 15 minutes on days 1 and 22, prednisone three times a day on days 1-28, and methotrexate intrathecally (IT) on days 1, 8, and 22. Patients in complete remission on day 43 proceed to maintenance, those in partial remission undergo biopsy then proceed to maintenance, and those with residual disease receive radiotherapy on regimen A concurrently with maintenance. Maintenance (day 1 is day 43 of Induction): Courses of intermediate dose methotrexate/leucovorin calcium and high dose cytarabine (ID MTX/CF/HD ARA-C) and modified APO alternate every 3 weeks. Patients receive a total of 15 courses (8 of ID MTX/CF/HD ARA-C and 7 of Modified APO). ID MTX/CF/HD ARA-C: Patients receive methotrexate IV over 24 hours on day 1, leucovorin calcium IV or orally every 6 hours on days 2 and 3, cytarabine IV over 48 hours on days 2 to 4, and methotrexate IT on day 1 of courses 1, 3, and 5. Filgrastim (G-CSF) is administered beginning on day 5 and continuing until blood counts recover. Modified APO: Patients receive vincristine IV on day 1, oral mercaptopurine on days 1-5, doxorubicin IV over 15 minutes on day 1, and oral prednisone three times a day on days 1-5. Arm II: Induction: Patients receive treatment as in arm I except that patients with CNS disease also receive methotrexate IT on days 15, 29, and 36. Maintenance (day 1 is day 43 of Induction): Modified APO: as in Arm I, with methotrexate administered on day 1 of courses 1, 3, and 5 (days 1-5 for patients with CNS disease). Courses repeat every 21 days for a total of 15 courses. Patients with CNS disease begin radiotherapy on Regimen B on week 2 of maintenance. Regimen A: Patients begin radiotherapy (5 days a week for 4.5 weeks) to residual tumor on day 1 of maintenance. Regimen B: Patients receive whole brain irradiation (5 days a week for 3.1 weeks) beginning on day 1 of maintenance. Patients are followed monthly for 6 months, every 3 months for 18 months, every 6 months for 3 years, and annually thereafter. PROJECTED ACCRUAL: A total of 242 patients will be accrued for this study over approximately 5.4 years.

Official Title
-----------------
A Phase III Study of Large Cell Lymphomas in Children and Adolescents: Comparison of APO vs APO + IDMTX/HDARA-C and Continuous vs Bolus Infusion of Doxorubicin

Conditions
-----------------
Lymphoma

Intervention / Treatment
-----------------
* Biological: filgrastim
* Drug: cytarabine
* Drug: doxorubicin hydrochloride
* Drug: leucovorin calcium
* Drug: mercaptopurine
* Drug: methotrexate
* Drug: prednisone
* Drug: vincristine sulfate
* Radiation: low-LET cobalt-60 gamma ray therapy
* Radiation: low-LET electron therapy
* Radiation: low-LET photon therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Previously untreated large cell lymphoma, including the following histologic designations: Rappaport classification Diffuse histiocytic Mixed lymphocytic-histiocytic Working Formulation classification Diffuse large cell, cleaved and/or noncleaved Immunoblastic Diffuse, mixed small and large cell Lukes-Collins classification Diffuse large cleaved Diffuse large noncleaved Immunoblastic T or B cell True histiocytic Updated Kiel classification Cytocentric large cell Centroblastic-centrocytic T-zone Lymphoepithelioid cell (Lennert's) Immunoblastic T or B cell Large cell anaplastic Pleomorphic Centroblastic-centrocytic, diffuse Malignant histiocytosis Murphy stage III/IV HIV-associated lymphoma eligible Any degree of bone marrow involvement eligible CNS disease eligible (such patients not randomized) PATIENT CHARACTERISTICS: Age: Under 22 Performance status: Not specified Hepatic: Not specified Renal: Not specified Other: Not pregnant or nursing Adequate contraception required of fertile patients PRIOR CONCURRENT THERAPY: No prior therapy

Ages Eligible for Study
-----------------
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Regimen A<br>Patients begin radiotherapy (5 days a week for 4.5 weeks) to residual tumor on day 1 of maintenance. | Biological: filgrastim<br> <br> * Other names: NSC #614629;Drug: cytarabine<br> <br> * Other names: NSC #63878;Drug: doxorubicin hydrochloride<br> <br> * Other names: NSC #123127;Drug: leucovorin calcium<br> <br> * Other names: NSC #3590;Drug: mercaptopurine<br> <br> * Other names: NSC #755;Drug: methotrexate<br> <br> * Other names: NSC #740;Drug: prednisone<br> <br> * Other names: NSC #10023;Drug: vincristine sulfate<br> <br> * Other names: NSC #67574;Radiation: low-LET cobalt-60 gamma ray therapy<br> <br> Radiation: low-LET electron therapy<br> <br> Radiation: low-LET photon therapy<br> <br> |
| Active Comparator: Regimen B<br>Patients receive whole brain irradiation (5 days a week for 3.1 weeks) beginning on day 1 of maintenance. Patients are followed monthly for 6 months, every 3 months for 18 months, every 6 months for 3 years, and annually thereafter. | Biological: filgrastim<br> <br> * Other names: NSC #614629;Drug: cytarabine<br> <br> * Other names: NSC #63878;Drug: doxorubicin hydrochloride<br> <br> * Other names: NSC #123127;Drug: leucovorin calcium<br> <br> * Other names: NSC #3590;Drug: mercaptopurine<br> <br> * Other names: NSC #755;Drug: methotrexate<br> <br> * Other names: NSC #740;Drug: prednisone<br> <br> * Other names: NSC #10023;Drug: vincristine sulfate<br> <br> * Other names: NSC #67574;Radiation: low-LET cobalt-60 gamma ray therapy<br> <br> Radiation: low-LET electron therapy<br> <br> Radiation: low-LET photon therapy<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event free survival | To study whether intermediate-dose methotrexate/high-dose Ara-C (ID MTX/HDAra-C), administered during the maintenance phase can improve the event free survival (EFS) of patients with advanced-stage large cell lymphoma (LCL). | Length of study | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
childhood diffuse large cell lymphoma, childhood immunoblastic large cell lymphoma, AIDS-related peripheral/systemic lymphoma, AIDS-related diffuse large cell lymphoma, AIDS-related immunoblastic large cell lymphoma, AIDS-related diffuse mixed cell lymphoma, stage III childhood large cell lymphoma, stage IV childhood large cell lymphoma