Lymphoma
Conditions
Keywords
stage I adult Hodgkin lymphoma, stage II adult Hodgkin lymphoma
Brief summary
This phase II trial studies how well chemotherapy based on positron emission tomography (PET) scan works in treating patients with stage I or stage II Hodgkin 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. Giving more than one drug (combination chemotherapy) may kill more cancer cells. Radiation therapy uses high energy x-rays to kill cancer cells. Giving combination chemotherapy together with radiation therapy may kill more cancer cells and allow doctors to save the part of the body where the cancer started. Comparing results of diagnostic procedures, such as PET scan, done before, during, and after chemotherapy may help doctors predict a patient's response to treatment and help plan the best treatment.
Detailed description
PRIMARY OBJECTIVES: I. To determine the progression-free survival (PFS) from enrollment for patients with non-bulky stage I and II Hodgkin lymphoma. II. To compare the PFS of patients who are PET positive versus PET negative following 2 cycles of doxorubicin hydrochloride, bleomycin, vinblastine, and dacarbazine (ABVD). SECONDARY OBJECTIVES: I. To evaluate the complete response (CR) rate of patients diagnosed with non-bulky stage I and II Hodgkin lymphoma following PET response-adapted chemotherapy with or without radiation therapy. II. To determine the predictive value of fludeoxyglucose (FDG) uptake using various semi-quantitative approaches, at baseline, after 2 cycles of AVBD and at completion of therapy. III. To determine the predictive value of volumetric changes on computed tomography (CT) vs 2-dimensional (2-D) analyses after 2 cycles and 4 cycles and compare with PET parameters with and without combination analyses (PET + dedicated CT data). IV. To compare the predictive value of metabolic parameters/changes that are measured both visually and semi-quantitatively, International Harmonization Project (IHP) criteria, 2-D and volumetric CT changes, molecular parameters, and conventional parameters, including International Prognostic Score (IPS). V. To assess whether elevated baseline circulating markers of inflammation (including soluble cluster of differentiation CD30 \[sCD\]30, soluble CD 163 \[CD163\], interleukin-10 (IL10), chemokine (C-C motif) ligand 17 (CCL17), and chemokine (C-C motif) ligand 22 \[CCL22\]) correlate with clinical response and PFS and PET scan results. VI. To assess whether persistent or recurrent elevated serial circulating markers of inflammation (including soluble CD30 \[sCD30\], soluble CD163 \[sCD163\], IL10, CCL17, or CCL22) correlate with relapse/progression or PET scan results. VII. To confirm independently useful tissue biomarkers for risk stratification in patients with non-bulky stage I and II Hodgkin lymphoma treated with this regimen. VIII. To compare mediastinal bulk on standing posterior-anterior (PA) and lateral chest x-ray (\> 0.33 maximum chest diameter) with chest CT (mass \> 10 cm). OUTLINE: ABVD CHEMOTHERAPY: Patients receive doxorubicin hydrochloride intravenously (IV) over 3-5 minutes, bleomycin sulfate IV over 3-5 minutes, vinblastine IV over 3-5 minutes, and dacarbazine IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for 2 courses. Patients then undergo PET scan. Patients achieving complete response (CR), partial response (PR), or stable disease (SD) with a negative PET scan receive 2 additional courses of ABVD chemotherapy in the absence of disease progression or unacceptable toxicity. Patients achieving CR, PR, or SD with a positive PET scan proceed to escalated BEACOPP chemotherapy. ESCALATED BEACOPP\* CHEMOTHERAPY: Patients receive doxorubicin hydrochloride IV over 3-5 minutes and cyclophosphamide IV over 60 minutes on day 1, etoposide IV over 45-60 minutes on days 1-3, procarbazine orally (PO) on days 1-7, prednisone PO on days 1-14, and bleomycin sulfate IV and vincristine IV on day 8. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Within 4-6 weeks after completion of BEACOPP chemotherapy, patients undergo involved-field radiotherapy (IFRT) 5 days a week for 3½ weeks. NOTE: \* HIV-positive patients receive standard BEACOPP instead of escalated BEACOPP. Patients undergo fludeoxyglucose F\^18 PET/CT scan at baseline, and within 8-10 days after completion of chemotherapy. Patients also undergo additional PET/CT scans within 3-4 weeks after completion of ABVD or within 12 weeks after completion of BEACOPP and IFRT. Patients with a negative PET scan proceed to follow up. Patients with a positive PET scan undergo biopsy\*\*. Patients with a negative biopsy proceed to follow up, and patients with a positive biopsy are treated at the discretion of the investigator. NOTE: \*\* Patients for whom biopsy is neither clinically appropriate nor medically feasible proceed to follow-up. Patients for whom biopsy is neither clinically indicated nor medically appropriate undergo a repeat PET/CT scan after 3 months. If PET/CT scan remains positive, patients undergo biopsy as above. After completion of study therapy, patients are followed up every 3 months for 1 year, every 6 months for 2-3 years, and then annually for a maximum of 5 years.
Interventions
BIOLOGICALBleomycin Sulfate
Given IV
DRUGDoxorubicin Hydrochloride
Given IV
DRUGProcarbazine Hydrochloride
Given PO
DRUGVinblastine Sulfate
Given IV
DRUGDacarbazine
Given IV
DRUGCyclophosphamide
Given IV
DRUGEtoposide phosphate
Given IV
DRUGprednisone
Given PO
DRUGRadiation Therapy
Undergo radiation therapy
RADIATIONFludeoxyglucose F-18
Undergo FDG PET/CT
PROCEDUREcomputed tomography
Undergo FDG PET/CT
PROCEDUREPositron Emission Tomography
Undergo FDG PET/CT
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed\* Hodgkin lymphoma * Clinical stage IA, IB, IIA, or IIB disease according to the modified Ann Arbor Staging Classification system * Subclassified according to the WHO modification of the Rye Classification * E extension allowed provided all other criteria have been met NOTE: \*Pathology materials must be submitted within 60 days of study registration. Core-needle biopsies are acceptable provided they contain adequate tissue for primary diagnosis and immunophenotyping. Fine-needle aspirates not allowed. If multiple specimens are available, submit the most recent. * No nodular lymphocyte-predominant Hodgkin lymphoma * No mediastinal mass \> 0.33 maximum intrathoracic diameter by standing postero-anterior chest x-ray or peripheral or retroperitoneal adenopathy \> 10 cm in its largest diameter * Measurable disease by physical examination or imaging studies * Any tumor mass measurable in two dimensions and \> 1 cm (or 1.5 cm if 0.5 cm slices are used, as in spiral CT scans) allowed * Lesions that are considered intrinsically non-measurable include: * Bone lesions * Leptomeningeal disease * Ascites * Pleural/pericardial effusion * Lymphangitis cutis/pulmonis * Abdominal masses that are not confirmed and followed by imaging techniques * Cystic lesions * Lesions that are situated in a previously irradiated area PATIENT CHARACTERISTICS: * Performance status 0-2 * ANC ≥ 1,000/μL * Platelet count ≥ 100,000/μL * Serum creatinine ≤ 2 mg/dL * Bilirubin ≤ 2 mg/dL * AST ≤ 2 times upper limit of normal * LVEF normal by ECHO or MUGA * DLCO ≥ 60% with no symptomatic pulmonary disease * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * Patients with known HIV allowed provided they have CD4 counts ≥ 350/mcL * Patients must not have multi-drug resistant HIV infections (i.e., concurrent AIDS-defining conditions) * An HIV test is required for patients with a history of IV drug abuse or any behavior associated with an increased risk of HIVinfection * No currently active second malignancy other than nonmelanoma skin cancers * Patients are not considered to have a currently active malignancy provided they have completed therapy and are considered by their physician to be at \< 30% risk of relapse PRIOR CONCURRENT THERAPY: * See Disease Characteristics * No prior chemotherapy or radiotherapy for Hodgkin lymphoma * 1 course of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) allowed and will be considered the first course
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) at 36-Months for Patients Who Received 4 Cycles of ABVD | 36 Months | The primary objective of this trial is to estimate the 3 year PFS in patients who received 4 cycles of ABVD. PFS for each patient is measured as the time from registration on trial to the first incident of death or progression. The PFS at 36 months is calculated as the number of patients who have a progression-free survival time greater than 36 months divided by the total number of patients that started treatment. For this endpoint, all patients that received 4 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) are included. |
| 36 Month Progression Free Survival Rate of Patients Receiving 4 Cycles of ABVD Versus Patients Receiving 2 Cycles of ABVD and 2 Cycles of BEACOPP and Radiation. | at 36 months | All patients received an initial 2-28 day cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) on Days 1 and 15. After the first 2 cycles of ABVD, PET/CT was performed and submitted for central review (cycle 2, days 23-25) and determined whether patients would receive 2 cycles of escalated BEACOPP and involved-field RT (IFRT) or an additional 2 cycles of ABVD. PFS for each patient is measured as the time from registration on trial to the first incident of death or progression. The PFS rate at 36 months is calculated as the number of patients who have a progression-free survival time greater than 36 months divided by the total number of patients that started treatment. For this endpoint, we compare the PFS rate between patients who received 4 cycles of ABVD and patients who received 2 cycles of ABVD and 2 cycles of IFRT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate | Up to 5 years | A Complete Response (CR) was defined as having the following conditions: 1. A complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. 2. In patients with a PET scan that was positive before therapy, a post-treatment residual mass of any size is permitted as long as it is PET-negative. A Complete Response rate was defined as the number of patients who achieved a CR divided by the number of patients that were eligible for analysis in each group. The CR rate was calculated for patients that completed 4 cycles of ABVD and for patients that completed 2 cycles of ABVD and 2 cycles of BEACOPP and IFRT. |
Countries
United States
Participant flow
Pre-assignment details
Therapy consisted of 2-28 day cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) on Days 1 and 15 of each cycle. PET/CT central review occurred after cycle 2. PET-negative patients received 2 additional cycles of ABVD. PET-positive patients received 2-21 day cycles of 3060-cGy involved-field RT (IFRT) and escalated BEACOPP.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (ABVD x2 Cycles) Therapy consisted of 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) on Days 1 and 15 of each cycle. A cycle is 28 days.\>\>
* Doxorubicin 25 mg/m2 IV on Days 1 and 15\>\>
* Bleomycin 10 units/m2 IV on Days 1 and 15\>\>
* Vinblastine 6 mg/m2 IV on Days 1 and 15\>\>
* Dacarbazine 375 mg/m2 IV infusion on Days 1 and 15\>\> \>\> PET/CT central review (cycle 2, days 23-25). Patients with a negative PET/CT (Deauville 1, 2, or 3) received 2 additional cycles of ABVD. \>\> \>\> Patients with positive PET received 2-21 day cycles of 3060-cGy involved-field RT (IFRT) and escalated BEACOPP:\>\>
Bleomycin 10 units/m2 IV on Day 8\>\> Etoposide 200 mg/m2 IV over 60 minutes on Days 1, 2 and 3 \>\> Doxorubicin 35 mg/m2 IV on Day 1 \>\> Cyclophosphamide 1250 mg/m2 IV over 60 minutes on Day 1 \>\> Vincristine 1.4 mg/m2 (maximum 2 mg) IV on Day 8 \>\> Procarbazine 100 mg/m2 (rounded to nearest 50 mg) orally on Days 1-7\>\> Prednisone 40 mg/m2 (rounded to nearest 5 mg) orally on Days 1-14 | 164 |
| Total | 164 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Initial ABVD Treatment (2 Cycles) | Ineligible | 6 | 0 | 0 |
| Initial ABVD Treatment (2 Cycles) | Withdrawal by Subject | 9 | 0 | 0 |
Baseline characteristics
| Characteristic | Treatment (ABVD x2 Cycles) |
|---|---|
| Age, Continuous | 31 years |
| Region of Enrollment United States | 164 participants |
| Sex: Female, Male Female | 76 Participants |
| Sex: Female, Male Male | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 135 | 0 / 14 |
| other Total, other adverse events | 8 / 15 | 131 / 135 | 13 / 14 |
| serious Total, serious adverse events | 1 / 15 | 12 / 135 | 2 / 14 |
Outcome results
Primary
36 Month Progression Free Survival Rate of Patients Receiving 4 Cycles of ABVD Versus Patients Receiving 2 Cycles of ABVD and 2 Cycles of BEACOPP and Radiation.
All patients received an initial 2-28 day cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) on Days 1 and 15. After the first 2 cycles of ABVD, PET/CT was performed and submitted for central review (cycle 2, days 23-25) and determined whether patients would receive 2 cycles of escalated BEACOPP and involved-field RT (IFRT) or an additional 2 cycles of ABVD. PFS for each patient is measured as the time from registration on trial to the first incident of death or progression. The PFS rate at 36 months is calculated as the number of patients who have a progression-free survival time greater than 36 months divided by the total number of patients that started treatment. For this endpoint, we compare the PFS rate between patients who received 4 cycles of ABVD and patients who received 2 cycles of ABVD and 2 cycles of IFRT.
Time frame: at 36 months
Population: All patients that completed an initial 2 cycles of ABVD were included in this endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (ABVD: 4 Cycles) | 36 Month Progression Free Survival Rate of Patients Receiving 4 Cycles of ABVD Versus Patients Receiving 2 Cycles of ABVD and 2 Cycles of BEACOPP and Radiation. | .91 proportion of participants |
| Escalated BEACOPP and Involved Field Radiation Therapy | 36 Month Progression Free Survival Rate of Patients Receiving 4 Cycles of ABVD Versus Patients Receiving 2 Cycles of ABVD and 2 Cycles of BEACOPP and Radiation. | .67 proportion of participants |
Primary
Progression-Free Survival (PFS) at 36-Months for Patients Who Received 4 Cycles of ABVD
The primary objective of this trial is to estimate the 3 year PFS in patients who received 4 cycles of ABVD. PFS for each patient is measured as the time from registration on trial to the first incident of death or progression. The PFS at 36 months is calculated as the number of patients who have a progression-free survival time greater than 36 months divided by the total number of patients that started treatment. For this endpoint, all patients that received 4 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) are included.
Time frame: 36 Months
Population: All patients that received 4 cycles of ABVD were included in this analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (ABVD: 4 Cycles) | Progression-Free Survival (PFS) at 36-Months for Patients Who Received 4 Cycles of ABVD | .91 proportion of patients |
Secondary
Complete Response Rate
A Complete Response (CR) was defined as having the following conditions: 1. A complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. 2. In patients with a PET scan that was positive before therapy, a post-treatment residual mass of any size is permitted as long as it is PET-negative. A Complete Response rate was defined as the number of patients who achieved a CR divided by the number of patients that were eligible for analysis in each group. The CR rate was calculated for patients that completed 4 cycles of ABVD and for patients that completed 2 cycles of ABVD and 2 cycles of BEACOPP and IFRT.
Time frame: Up to 5 years
Population: Two patients began a third cycle of ABVD and were not eligible for response evaluation (one withdrew and one was lost to follow up). Fourteen patients started BEACOPP treatment, and one patient was lost to follow-up and not included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (ABVD: 4 Cycles) | Complete Response Rate | .97 proportion of participants |
| Escalated BEACOPP and Involved Field Radiation Therapy | Complete Response Rate | .85 proportion of participants |