Treating Young Patients With Newly Diagnosed, Low Stage, Lymphocyte Predominant Hodgkin Disease

Study Overview
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Brief Summary
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This clinical trial is studying how well surgery and/or combination chemotherapy with or without radiation therapy or observation only work in treating young patients with newly diagnosed stage I or stage II lymphocyte predominant Hodgkin disease (LPHD). Surgery may be an effective treatment for LPHD. Drugs used in chemotherapy, such as doxorubicin, vincristine, prednisone, and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill cancer cells. Giving more than one drug (combination chemotherapy) with or without radiation therapy may kill more cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To preserve the excellent cure rate in patients with lymphocyte predominant Hodgkin disease (LPHD) while employing a treatment strategy that minimizes the exposure to chemotherapy and radiation therapy in appropriate patients. II. To estimate the proportion of stage I patients (with a single involved lymph node that is totally resected) who can be cured with surgery alone. III. To estimate the proportions of stage I unresected, stage I resected (whose disease has recurred after observation), and stage II LPHD patients who can be cured with adriamycin (doxorubicin)/vincristine/prednisone/cyclophosphamide (AV-PC) x 3, with involved field radiation therapy (IFRT) for those who are not in a CR after chemotherapy. IV. To reduce the potential for long-term toxicity of LPHD treatment. OUTLINE: This is a pilot study. Patients with stage IA disease who underwent confirmed complete resection of a single involved lymph node at diagnosis undergo observation only*. Patients with stage IA disease who underwent possible complete resection of a single involved lymph node at diagnosis undergo imaging at 6-7 weeks after surgery. Patients with a confirmed complete resection by imaging undergo observation only*. Patients who do not demonstrate complete resection by imaging proceed to combination chemotherapy with or without radiotherapy. Patients with stage IA disease who underwent a fine needle aspiration of a single involved lymph node OR an incomplete resection of a single involved lymph node at diagnosis may undergo a second surgery to achieve complete resection. Patients who undergo complete resection during the second surgery undergo imaging at 6-7 weeks after surgery. Patients with a confirmed complete resection by imaging undergo observation only*. Patients who do not undergo a second surgery OR do not achieve complete resection with the second surgery proceed to combination chemotherapy with or without radiotherapy. Patients with stage IA disease with involvement of more than 1 lymph node OR stage IIA disease proceed directly to combination chemotherapy with or without radiotherapy. NOTE: *Patients with recurrent disease after observation only undergo biopsy and restaging and then proceed to combination chemotherapy with or without radiotherapy. (AS OF AMENDMENT #4, THE TREATMENT ARM FOR PATIENTS WHOSE CANCER RECURRED AFTER OBSERVATION ALONE IS NOW CLOSED) COMBINATION CHEMOTHERAPY: Patients receive doxorubicin hydrochloride intravenously (IV) over 10-30 minutes and cyclophosphamide IV over 1 hour on day 1, vincristine IV over 1 minute on days 1 and 8, and prednisone orally (PO) or IV two or three times daily on days 1-7. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve complete response (CR) after 3 courses of therapy proceed to follow-up. Patients who do not achieve a CR proceed to involved-field radiotherapy. INVOLVED-FIELD RADIOTHERAPY (IFRT): Beginning within 3 weeks after completion of combination chemotherapy, patients undergo IFRT once daily, 5 days a week for 2.8 weeks (14 treatments). Patients are followed every 3 months for 2 years, every 6 months for 3 years, annually for 5 years, and then every 5 years for 10 years.

Official Title
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Treatment of Children With Newly-Diagnosed Low Stage Lymphocyte Predominant Hodgkin Disease (LPHD)

Conditions
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Ann Arbor Stage I Childhood Hodgkin Lymphoma, Ann Arbor Stage II Childhood Hodgkin Lymphoma, Childhood Nodular Lymphocyte Predominant B-Cell Lymphoma

Intervention / Treatment
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* Procedure: Conventional Surgery
* Drug: Cyclophosphamide
* Drug: Doxorubicin Hydrochloride
* Drug: Prednisone
* Radiation: Radiation Therapy
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with newly diagnosed, previously untreated, biopsy-proven lymphocyte predominant Hodgkin disease (LPHD) are eligible for this protocol as follows: Diagnosis of LPHD must be made using the Revised European American Lymphoma (REAL)/World Health Organization (WHO) classification criteria and will be confirmed by rapid pathology central review Clinical stages as follows: Stage IA without bulk disease Stage IIA without bulk disease Patients with B symptoms or bulk disease are NOT eligible for this study Slides for rapid central pathology review must be sent to the Biopathology Center (BPC) Serum glutamic oxalo-acetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 times upper limit of normal (ULN) Total bilirubin =< 1.5 times ULN Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min Creatinine based on age/gender as follows: No greater than 0.4 mg/dL (for patients 1 to 5 months of age) No greater than 0.5 mg/dL (for patients 6 to 11 months of age) No greater than 0.6 mg/dL (for patients 1 year of age) No greater than 0.8 mg/dL (for patients 2 to 5 years of age) No greater than 1.0 mg/dL (for patients 6 to 9 years of age) No greater than 1.2 mg/dL (for patients 10 to 12 years of age) No greater than 1.4 mg/dL (for female patients >= 13 years of age) No greater than 1.5 mg/dL (for male patients 13 to 15 years of age) No greater than 1.7 mg/dL (for male patients >= 16 years of age) Shortening fraction of >= 27% by echocardiogram or ejection fraction of >= 50% by multigated radionuclide angiogram (MUGA) Lactating females must agree that they will not breastfeed a child if they are to receive chemotherapy or radiation treatment* Female patients of childbearing potential must have a negative pregnancy test if they are to receive chemotherapy or radiation treatment* Males and females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method if they are to receive chemotherapy or radiation treatment* Note: *Pregnant or breastfeeding women with stage I, single involved lymph node and confirmed (by Quality Assurance Review Center [QARC ]) total resection, are eligible for the observation arm only; no chemotherapy or radiation treatment will be administered to pregnant or breastfeeding women No prior chemotherapy More than 30 days since prior systemic corticosteroids No prior radiotherapy All patients and/or their parents or legal guardians must sign a written informed consent

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (surgery, combination chemotherapy, radiotherapy)<br>COMBINATION CHEMOTHERAPY: Patients receive doxorubicin hydrochloride IV over 10-30 minutes and cyclophosphamide IV over 1 hour on day 1, vincristine IV over 1 minute on days 1 and 8, and prednisone PO or IV two or three times daily on days 1-7. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve CR after 3 courses of therapy proceed to follow-up. Patients who do not achieve a CR proceed to involved-field radiotherapy. IFRT: Beginning within 3 weeks after completion of combination chemotherapy, patients undergo IFRT once daily, 5 days a week for 2.8 weeks (14 treatments). | Procedure: Conventional Surgery<br>* Undergo surgery<br>Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Prednisone<br>* Given IV or PO<br>* Other names: SK-Prednisone;Radiation: Radiation Therapy<br>* Undergo IFRT<br>* Other names: Therapy, Radiation;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Failure-free Survival (FFS) | The time to a treatment (strategy) failure, where failure includes one of the following occurrences as a first event: disseminated disease (> Stage I/II) progression or recurrence at any time, local disease progression or recurrence anytime during or after treatment with AV-PC +/- IFRT, occurrence of a second malignant neoplasm, death from any cause. | At 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival | Failure includes one of the following occurrences as a first event: relapse/progression or second malignancy from enrollment. | At 5 years | 
| Cure by Surgery Alone in Stage I Resected Patients | To estimate the proportion of Stage I patients (with a single involved lymph node that is totally resected) who can be cured with surgery alone. | At 2 years | 
| Cure by AV-PC x 3 or AV-PC x 3 + IFRT for Stage I Unresected, Stage I Resected Whose Disease Recurred, and Stage II Patients | To estimate the proportions of Stage I unresected, Stage I resected (whose disease has recurred after observation), and Stage II LPHD patients who can be cured with AV-PC x 3, with IFRT for those who are not in a CR after chemotherapy. | At 5 years | 
| Grade 3 or 4 Toxicity |  | Any time during chemoradiotherapy, up to the end of 3-cycles of AV-PC induction. Each cycle is 21 days. |