Childhood Favorable Prognosis Hodgkin Lymphoma, Childhood Lymphocyte Depletion Hodgkin Lymphoma, Childhood Mixed Cellularity Hodgkin Lymphoma, Childhood Nodular Sclerosis Hodgkin Lymphoma, Stage I Childhood Hodgkin Lymphoma, Stage II Childhood Hodgkin Lymphoma
Conditions
Brief summary
This phase III trial is studying how well combination chemotherapy works when given before radiation therapy and/or additional chemotherapy in treating young patients with newly diagnosed Hodgkin's lymphoma. Drugs used in chemotherapy 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) and giving them together with radiation therapy may kill more cancer cells.
Detailed description
OBJECTIVES: I. Investigate the paradigm of response-based therapy for low-risk Hodgkin's lymphoma by eliminating involved-field radiotherapy (IFRT) in patients who achieve a complete remission (CR) after initial chemotherapy. II. Investigate whether 3 courses of doxorubicin hydrochloride, vincristine, prednisone, and cyclophosphamide (AV-PC) for the treatment of low-risk Hodgkin's lymphoma is sufficient to induce CR in at least 80% of patients. III. Investigate whether patients who experience a low-risk relapse after initial treatment with chemotherapy alone can be successfully treated with a salvage regimen comprising ifosfamide and vinorelbine ditartrate with dexamethasone, etoposide phosphate, cisplatin, and cytarabine (IV/DECA) and IFRT. IV. Maintain the overall survival for patients with low-risk Hodgkin's lymphoma at or above 97%. V. Determine the prognostic significance of very early response as measured by fludeoxyglucose-positron emission tomography (FDG-PET) or gallium after the first course of chemotherapy. VI. Evaluate the prognostic significance of elevation of erythrocyte sedimentation rate and C-reactive protein at the time of diagnosis in patients with low-risk Hodgkin's lymphoma on CR rate and relapse rate after chemotherapy alone. VII. Determine the frequency and severity of late effects of therapy, including thyroid dysfunction, infertility, cardiotoxicity, and second malignant neoplasms. OUTLINE: This is a multicenter study. INITIAL CHEMOTHERAPY: Patients receive doxorubicin hydrochloride intravenously (IV) over 10-30 minutes and cyclophosphamide IV over 1 hour on days 1-2, vincristine IV on days 1 and 8, prednisone orally (PO) on days 1-7, and filgrastim (G-CSF) subcutaneously (SC) on days 3-7 and 9-14. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving complete remission (CR) proceed to observation. Patients achieving partial remission proceed to radiotherapy. Patients who have a low-risk relapse after achieving CR on initial chemotherapy proceed to salvage chemotherapy followed by radiotherapy. Patients who have stable disease or disease progression go off study. SALVAGE CHEMOTHERAPY: Patients receive ifosfamide IV continuously on days 1-4, vinorelbine ditartrate IV over 6-10 minutes on days 1-5, and G-CSF SC or IV beginning on day 6 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. Patients then receive dexamethasone IV over 15 minutes every 12 hours, etoposide phosphate IV over 3 hours every 12 hours, and cytarabine IV over 3 hours every 12 hours on days 1 and 2; cisplatin IV over 6 hours on day 1; and G-CSF SC or IV beginning on day 3 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. Patients then proceed to radiotherapy. INVOLVED-FIELD RADIOTHERAPY (IFRT): Beginning 4 weeks after completion of chemotherapy, patients undergo IFRT once daily, 5 days a week, for 2.8 weeks. Patients who do not achieve CR go off study. After completion of study treatment, patients are followed periodically for up to 10 years.
Interventions
Given IV or subcutaneously
Undergo radiation therapy
Given IV
Given IV
Given orally
Given IV
Given IV
Given IV
Given IV
Given IV
Given IV
Given IV
Sponsors
Study design
Eligibility
Inclusion criteria
* Histologically confirmed Hodgkin's lymphoma meeting the following criteria: * Newly diagnosed disease * Stage IA OR stage IIA without bulky disease * No lymphocyte-predominant histology * Staging on this study will be determined by the clinical stage; surgical staging is strongly discouraged, except for the rare situation of equivocal imaging studies below the diaphragm * Patients may not have received any previous chemotherapy or radiation therapy; patients may not have received systemic corticosteroids within 30 days of enrollment on this protocol; steroids used for treatment of contrast agent allergy required for computed tomography (CT) scans are acceptable * Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^3 * Total bilirubin =\< 1.5 x normal * Alanine (ALT) =\< 2.5 x normal * Shortening fraction \>= 27% by echocardiogram OR ejection fraction \>= 50% by multi-gated acquisition (MUGA) * No pathologic prolongation of QTc interval on 12-lead electrocardiography (ECG) * Female patients of childbearing potential must have a negative pregnancy test * Lactating females must agree that they will not breastfeed a child while on this study * Fertile patients must use effective contraception * Males and females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method * All patients and/or their parents or legal guardians must sign a written informed consent * All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event Free Survival Without Receiving Radiation Therapy (EFSnoRT). | At 60 months | Survival is defined as the minimum time from study entry to requirement for additional chemotherapy and IFRT for retrieval, occurrence of a second malignant neoplasm, or death from any cause. Patients without report of such events where censored at last contact. Patients who achieve less than CR after 3 cycles of AV-PC will require IFRT and hence will satisfy this definition at the time of response evaluation. Patients who achieve a CR but who relapse will receive addition chemotherapy and IFRT or intense retrieval and hence will satisfy this definition at the time of the first relapse of Hodgkin disease. This endpoint will be used to compute event free survival without receiving radiation therapy (EFSnoRT). |
| Intensive Therapy Free Survival (ITFS). | At 60 months | Survival is defined as the minimum time from study entry to a relapse of higher risk at any time, any relapse following treatment with protocol mandated IFRT, death from any cause, or the occurrence of a second malignant neoplasm. This will be used to compute intensive therapy free survival (ITFS). Patients without report of such events where censored at last contact. This differs from traditional EFS in that relapse after AVPC\* x3 therapy alone that does not place the patient in a higher risk category is not considered a treatment failure. In this definition, higher-risk relapse refers to relapse involving sites and extent of disease that place the patient in the current COG definition of intermediate or high-risk disease. If a patient with CR who experiences a LR relapse is not retreated with protocol-mandated chemotherapy and IFRT, subsequent disease relapses will nevertheless be counted in the analysis of the treatment strategy. |
| Event Free Survival (EFS) | At 60 months | Survival is defined as the minimum time from study entry to a relapse of any kind, death from any cause, or occurrence of a second malignant neoplasm. Patients without report of such events where censored at last contact. This will be used to compute event free survival (EFS). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | At 60 months | Survival is defined as time from study entry to death due to any cause. Patients alive at last contact where censored at last contact. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Doxorubicin, Vincristine, Cyclophosphamide and Filgrastim Treatment consists of 3 cycles of Doxorubicin hydrochloride IV (25 mg/m2) days 1 & 2, Vincristine sulfate IV (1.4 mg/m2 \[max 2.8 mg\]) Days 1 & 8, Prednisone orally (40 mg/m2) Days 1-7, Cyclophosphamide IV (600 mg/m2) Days 1 & 2, Filgrastim by mouth or IV (5 micrograms/kg/dose) 24 hours after Cyclophosphamide complete. See detailed description for remainder of therapy.
radiation therapy: Undergo radiation therapy
doxorubicin hydrochloride: Given IV
vincristine sulfate: Given IV
prednisone: Given orally
cyclophosphamide: Given IV
ifosfamide: Given IV
vinorelbine tartrate: Given IV
dexamethasone: Given IV
etoposide phosphate: Given IV
cisplatin: Given IV
cytarabine: Given IV
filgrastim: Given IV or subcutaneously | 287 |
| Total | 287 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Ineligible | 9 |
| Overall Study | Lack of Efficacy | 62 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Doxorubicin, Vincristine, Cyclophosphamide and Filgrastim |
|---|---|
| Age, Categorical <=18 years | 272 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants |
| Age, Continuous | 15 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 43 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 227 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 17 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants |
| Race (NIH/OMB) Asian | 8 Participants |
| Race (NIH/OMB) Black or African American | 29 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 27 Participants |
| Race (NIH/OMB) White | 220 Participants |
| Region of Enrollment Australia | 3 participants |
| Region of Enrollment Canada | 25 participants |
| Region of Enrollment Israel | 1 participants |
| Region of Enrollment Mexico | 1 participants |
| Region of Enrollment New Zealand | 2 participants |
| Region of Enrollment Puerto Rico | 4 participants |
| Region of Enrollment Switzerland | 1 participants |
| Region of Enrollment United States | 250 participants |
| Sex: Female, Male Female | 160 Participants |
| Sex: Female, Male Male | 127 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 80 / 278 |
| serious Total, serious adverse events | 2 / 278 |
Outcome results
Event Free Survival (EFS)
Survival is defined as the minimum time from study entry to a relapse of any kind, death from any cause, or occurrence of a second malignant neoplasm. Patients without report of such events where censored at last contact. This will be used to compute event free survival (EFS).
Time frame: At 60 months
Population: Eligible (n=278). Follow-up for censored patients (n=223) is 75 months (range: 4.7 to 108 months).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Event Free Survival (EFS) | 0.79 Probability of survival |
Event Free Survival Without Receiving Radiation Therapy (EFSnoRT).
Survival is defined as the minimum time from study entry to requirement for additional chemotherapy and IFRT for retrieval, occurrence of a second malignant neoplasm, or death from any cause. Patients without report of such events where censored at last contact. Patients who achieve less than CR after 3 cycles of AV-PC will require IFRT and hence will satisfy this definition at the time of response evaluation. Patients who achieve a CR but who relapse will receive addition chemotherapy and IFRT or intense retrieval and hence will satisfy this definition at the time of the first relapse of Hodgkin disease. This endpoint will be used to compute event free survival without receiving radiation therapy (EFSnoRT).
Time frame: At 60 months
Population: Eligible (n=278) and evaluable response and review of response, n=275. Follow-up for censored patients (n=138) is 76 months (range: 1.8 to 108 months).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Event Free Survival Without Receiving Radiation Therapy (EFSnoRT). | 0.49 Probability of survival |
Intensive Therapy Free Survival (ITFS).
Survival is defined as the minimum time from study entry to a relapse of higher risk at any time, any relapse following treatment with protocol mandated IFRT, death from any cause, or the occurrence of a second malignant neoplasm. This will be used to compute intensive therapy free survival (ITFS). Patients without report of such events where censored at last contact. This differs from traditional EFS in that relapse after AVPC\* x3 therapy alone that does not place the patient in a higher risk category is not considered a treatment failure. In this definition, higher-risk relapse refers to relapse involving sites and extent of disease that place the patient in the current COG definition of intermediate or high-risk disease. If a patient with CR who experiences a LR relapse is not retreated with protocol-mandated chemotherapy and IFRT, subsequent disease relapses will nevertheless be counted in the analysis of the treatment strategy.
Time frame: At 60 months
Population: Eligible (n=278) and evaluable response and review of response, n=275. Follow-up for censored patients (n=245) is 76 months (range: 4.7 to 109 months).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Intensive Therapy Free Survival (ITFS). | 0.89 Probability of survival |
Overall Survival
Survival is defined as time from study entry to death due to any cause. Patients alive at last contact where censored at last contact.
Time frame: At 60 months
Population: Eligible (n=278). Follow-up for censored patients (n=277) is 76 months (range: 4.7 to 109 months).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Overall Survival | 0.99 Probability of survival |