Brief Summary
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. Peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy and radiation and kill more cancer cells. It is not yet known whether chemoradiotherapy plus peripheral stem cell transplantation is more effective than combination chemotherapy alone in treating non-Hodgkin's lymphoma.
PURPOSE: This randomized phase III trial is studying chemoradiotherapy and peripheral stem cell transplantation to see how well they work compared to combination chemotherapy in treating patients with stage II, stage III, or stage IV non-Hodgkin's lymphoma.
PURPOSE: This randomized phase III trial is studying chemoradiotherapy and peripheral stem cell transplantation to see how well they work compared to combination chemotherapy in treating patients with stage II, stage III, or stage IV non-Hodgkin's lymphoma.
Brief Title
SWOG-9704 Chemoradiotherapy and Peripheral Stem Cell Transplantation Compared With Combination Chemotherapy in Treating Patients With Non-Hodgkin's Lymphoma
Detailed Description
OBJECTIVES:
* Compare the overall survival and progression-free survival of patients with intermediate- or high-grade non-Hodgkin's lymphoma treated with high-dose chemoradiotherapy and autologous peripheral blood stem cell transplantation (APBSCT) vs conventional dose cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (or CHOP plus rituximab for CD20+ disease) with possible late APBSCT.
* Compare the toxic effects of these regimens in this patient population.
OUTLINE: This is a randomized study. Patients are stratified according to disease risk (intermediate-high vs high).
Patients receive CHOP chemotherapy comprising cyclophosphamide IV over 15 minutes, doxorubicin IV, and vincristine IV on day 1 and oral prednisone on days 1-5. Patients with CD20-positive disease also receive rituximab IV on day 1 (or day 0 during course 1 only). Treatment repeats every 3 weeks for 5 courses in the absence of disease progression or unacceptable toxicity.
Within 35 days of completing the fifth course, patients with partial or complete response are randomized to one of two treatment arms.
* Arm I: Patients receive CHOP (or CHOP plus rituximab \[CHOP-R\]) as above. Treatment repeats every 3 weeks for 3 additional courses. After completion of chemotherapy, patients are encouraged to undergo harvest of peripheral blood stem cells (PBSC) for possible use at time of relapse. After completion of 8 courses, patients receive no additional therapy until disease progression or biopsy-proven disease.
* Arm II: Patients receive one additional course of CHOP/CHOP-R followed by filgrastim (G-CSF), sargramostim (GM-CSF), or other colony-stimulating factors used singly or in combination according to center preference. PBSC are harvested and selected for CD34+ cells. Patients under age 61 receive one of two preparative regimens: a total body irradiation (TBI)-based regimen comprising irradiation administered twice daily on days -8 to -5, etoposide IV over 4 hours on day -4, and cyclophosphamide IV over 1 hour on day -2 OR carmustine IV over 2 hours on days -6 to -4 and etoposide and cyclophosphamide as in the TBI-based regimen. Patients age 61 to 65 receive the augmented regimen comprising carmustine, etoposide, and cyclophosphamide as above. Patients receive involved field radiotherapy prior to the preparative regimen only if there is biopsy-proven residual bulk disease and at the discretion of the center. PBSC are reinfused 36-48 hours after completion of cyclophosphamide. If both bone marrow and PBSC are harvested, bone marrow is reinfused on day 0 and then PBSC are reinfused either the same day or the following day.
Patients are followed every 6 months for 2 years and then annually thereafter.
PROJECTED ACCRUAL: Approximately 360 patients (at least 135 per treatment arm) will be accrued for this study within 5 years.
* Compare the overall survival and progression-free survival of patients with intermediate- or high-grade non-Hodgkin's lymphoma treated with high-dose chemoradiotherapy and autologous peripheral blood stem cell transplantation (APBSCT) vs conventional dose cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (or CHOP plus rituximab for CD20+ disease) with possible late APBSCT.
* Compare the toxic effects of these regimens in this patient population.
OUTLINE: This is a randomized study. Patients are stratified according to disease risk (intermediate-high vs high).
Patients receive CHOP chemotherapy comprising cyclophosphamide IV over 15 minutes, doxorubicin IV, and vincristine IV on day 1 and oral prednisone on days 1-5. Patients with CD20-positive disease also receive rituximab IV on day 1 (or day 0 during course 1 only). Treatment repeats every 3 weeks for 5 courses in the absence of disease progression or unacceptable toxicity.
Within 35 days of completing the fifth course, patients with partial or complete response are randomized to one of two treatment arms.
* Arm I: Patients receive CHOP (or CHOP plus rituximab \[CHOP-R\]) as above. Treatment repeats every 3 weeks for 3 additional courses. After completion of chemotherapy, patients are encouraged to undergo harvest of peripheral blood stem cells (PBSC) for possible use at time of relapse. After completion of 8 courses, patients receive no additional therapy until disease progression or biopsy-proven disease.
* Arm II: Patients receive one additional course of CHOP/CHOP-R followed by filgrastim (G-CSF), sargramostim (GM-CSF), or other colony-stimulating factors used singly or in combination according to center preference. PBSC are harvested and selected for CD34+ cells. Patients under age 61 receive one of two preparative regimens: a total body irradiation (TBI)-based regimen comprising irradiation administered twice daily on days -8 to -5, etoposide IV over 4 hours on day -4, and cyclophosphamide IV over 1 hour on day -2 OR carmustine IV over 2 hours on days -6 to -4 and etoposide and cyclophosphamide as in the TBI-based regimen. Patients age 61 to 65 receive the augmented regimen comprising carmustine, etoposide, and cyclophosphamide as above. Patients receive involved field radiotherapy prior to the preparative regimen only if there is biopsy-proven residual bulk disease and at the discretion of the center. PBSC are reinfused 36-48 hours after completion of cyclophosphamide. If both bone marrow and PBSC are harvested, bone marrow is reinfused on day 0 and then PBSC are reinfused either the same day or the following day.
Patients are followed every 6 months for 2 years and then annually thereafter.
PROJECTED ACCRUAL: Approximately 360 patients (at least 135 per treatment arm) will be accrued for this study within 5 years.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Lymphoma
Eligibility Criteria
DISEASE CHARACTERISTICS:
* Histologically proven intermediate- or high-grade non-Hodgkin's lymphoma
* Ann Arbor classification of "bulky" stage II, III, or IV
* Must be classified as high-intermediate or high-risk according to International Age Adjusted Index
* Bidimensionally measurable disease
* No lymphoblastic, transformed, or mantle cell lymphomas
* No CNS involvement by lymphoma
* CD20 status confirmed by immunocytochemistry or flow cytometry
* Must have either bilateral or unilateral bone marrow aspiration and biopsy ≥ 42 days before first course of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy (or CHOP plus rituximab \[CHOP-R\] for CD20+ disease) OR within 42 days prior to registration if CHOP/CHOP-R therapy has not begun
* Must have bilateral bone marrow aspiration and biopsy within 28 days of randomization
* Bone marrow involvement with lymphoma is allowed, provided there is an improvement of at least 50% if used as an evaluable site of disease
* No prior lymphoma, Hodgkin's lymphoma, myelodysplastic syndromes, or leukemia NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.
PATIENT CHARACTERISTICS:
Age:
* 15 to 65
Performance status:
* Not specified
Life expectancy:
* Not specified
Hematopoietic:
* Not specified
Hepatic:
* Bilirubin no greater than 1.5 times upper limit of normal (ULN)
* No nonlymphoma-related hepatic dysfunction
Renal:
* Creatinine no greater than 2 times ULN
* Creatinine clearance at least 60 mL/min
* No nonlymphoma-related renal dysfunction
* No history of grade 3 hemorrhagic cystitis due to cyclophosphamide
Cardiovascular:
* No coronary artery disease, cardiomyopathy, congestive heart failure, or dysrhythmia requiring therapy
* MUGA scan or 2-D echocardiogram required if patient's history is questionable
* Ejection fraction normal
Pulmonary:
* DLCO or FEV_1 at least 60% of predicted
Other:
* Not pregnant or nursing
* Fertile patients must use effective contraception
* HIV negative
* No other malignancy within the past 5 years except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
* No allergy to etoposide
* No active bacterial, fungal, or viral infection
PRIOR CONCURRENT THERAPY:
Biologic therapy:
* No prior monoclonal antibody therapy for lymphoma except if included in a single course of CHOP/CHOP-R
Chemotherapy:
* No prior chemotherapy for lymphoma except for a single course of CHOP/CHOP-R\* NOTE: \*Prednisone or other corticosteroids not considered prior chemotherapy
Endocrine therapy:
* See Chemotherapy
* Prior corticosteroids allowed
Radiotherapy:
* No prior radiotherapy for lymphoma
* No prior thoracic radiotherapy or radiotherapy greater than 2,000 cGy to any other site
Surgery:
* Not specified
* Histologically proven intermediate- or high-grade non-Hodgkin's lymphoma
* Ann Arbor classification of "bulky" stage II, III, or IV
* Must be classified as high-intermediate or high-risk according to International Age Adjusted Index
* Bidimensionally measurable disease
* No lymphoblastic, transformed, or mantle cell lymphomas
* No CNS involvement by lymphoma
* CD20 status confirmed by immunocytochemistry or flow cytometry
* Must have either bilateral or unilateral bone marrow aspiration and biopsy ≥ 42 days before first course of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy (or CHOP plus rituximab \[CHOP-R\] for CD20+ disease) OR within 42 days prior to registration if CHOP/CHOP-R therapy has not begun
* Must have bilateral bone marrow aspiration and biopsy within 28 days of randomization
* Bone marrow involvement with lymphoma is allowed, provided there is an improvement of at least 50% if used as an evaluable site of disease
* No prior lymphoma, Hodgkin's lymphoma, myelodysplastic syndromes, or leukemia NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.
PATIENT CHARACTERISTICS:
Age:
* 15 to 65
Performance status:
* Not specified
Life expectancy:
* Not specified
Hematopoietic:
* Not specified
Hepatic:
* Bilirubin no greater than 1.5 times upper limit of normal (ULN)
* No nonlymphoma-related hepatic dysfunction
Renal:
* Creatinine no greater than 2 times ULN
* Creatinine clearance at least 60 mL/min
* No nonlymphoma-related renal dysfunction
* No history of grade 3 hemorrhagic cystitis due to cyclophosphamide
Cardiovascular:
* No coronary artery disease, cardiomyopathy, congestive heart failure, or dysrhythmia requiring therapy
* MUGA scan or 2-D echocardiogram required if patient's history is questionable
* Ejection fraction normal
Pulmonary:
* DLCO or FEV_1 at least 60% of predicted
Other:
* Not pregnant or nursing
* Fertile patients must use effective contraception
* HIV negative
* No other malignancy within the past 5 years except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
* No allergy to etoposide
* No active bacterial, fungal, or viral infection
PRIOR CONCURRENT THERAPY:
Biologic therapy:
* No prior monoclonal antibody therapy for lymphoma except if included in a single course of CHOP/CHOP-R
Chemotherapy:
* No prior chemotherapy for lymphoma except for a single course of CHOP/CHOP-R\* NOTE: \*Prednisone or other corticosteroids not considered prior chemotherapy
Endocrine therapy:
* See Chemotherapy
* Prior corticosteroids allowed
Radiotherapy:
* No prior radiotherapy for lymphoma
* No prior thoracic radiotherapy or radiotherapy greater than 2,000 cGy to any other site
Surgery:
* Not specified
Inclusion Criteria
DISEASE CHARACTERISTICS:
* Histologically proven intermediate- or high-grade non-Hodgkin's lymphoma
* Ann Arbor classification of "bulky" stage II, III, or IV
* Must be classified as high-intermediate or high-risk according to International Age Adjusted Index
* Bidimensionally measurable disease
* No lymphoblastic, transformed, or mantle cell lymphomas
* No CNS involvement by lymphoma
* CD20 status confirmed by immunocytochemistry or flow cytometry
* Must have either bilateral or unilateral bone marrow aspiration and biopsy ≥ 42 days before first course of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy (or CHOP plus rituximab \[CHOP-R\] for CD20+ disease) OR within 42 days prior to registration if CHOP/CHOP-R therapy has not begun
* Must have bilateral bone marrow aspiration and biopsy within 28 days of randomization
* Bone marrow involvement with lymphoma is allowed, provided there is an improvement of at least 50% if used as an evaluable site of disease
* No prior lymphoma, Hodgkin's lymphoma, myelodysplastic syndromes, or leukemia NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.
PATIENT CHARACTERISTICS:
Age:
* 15 to 65
Performance status:
* Not specified
Life expectancy:
* Not specified
Hematopoietic:
* Not specified
Hepatic:
* Bilirubin no greater than 1.5 times upper limit of normal (ULN)
* No nonlymphoma-related hepatic dysfunction
Renal:
* Creatinine no greater than 2 times ULN
* Creatinine clearance at least 60 mL/min
* No nonlymphoma-related renal dysfunction
* No history of grade 3 hemorrhagic cystitis due to cyclophosphamide
Cardiovascular:
* No coronary artery disease, cardiomyopathy, congestive heart failure, or dysrhythmia requiring therapy
* MUGA scan or 2-D echocardiogram required if patient's history is questionable
* Ejection fraction normal
Pulmonary:
* DLCO or FEV_1 at least 60% of predicted
Other:
* Not pregnant or nursing
* Fertile patients must use effective contraception
* HIV negative
* No other malignancy within the past 5 years except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
* No allergy to etoposide
* No active bacterial, fungal, or viral infection
PRIOR CONCURRENT THERAPY:
Biologic therapy:
* No prior monoclonal antibody therapy for lymphoma except if included in a single course of CHOP/CHOP-R
Chemotherapy:
* No prior chemotherapy for lymphoma except for a single course of CHOP/CHOP-R\* NOTE: \*Prednisone or other corticosteroids not considered prior chemotherapy
Endocrine therapy:
* See Chemotherapy
* Prior corticosteroids allowed
Radiotherapy:
* No prior radiotherapy for lymphoma
* No prior thoracic radiotherapy or radiotherapy greater than 2,000 cGy to any other site
Surgery:
* Not specified
* Histologically proven intermediate- or high-grade non-Hodgkin's lymphoma
* Ann Arbor classification of "bulky" stage II, III, or IV
* Must be classified as high-intermediate or high-risk according to International Age Adjusted Index
* Bidimensionally measurable disease
* No lymphoblastic, transformed, or mantle cell lymphomas
* No CNS involvement by lymphoma
* CD20 status confirmed by immunocytochemistry or flow cytometry
* Must have either bilateral or unilateral bone marrow aspiration and biopsy ≥ 42 days before first course of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy (or CHOP plus rituximab \[CHOP-R\] for CD20+ disease) OR within 42 days prior to registration if CHOP/CHOP-R therapy has not begun
* Must have bilateral bone marrow aspiration and biopsy within 28 days of randomization
* Bone marrow involvement with lymphoma is allowed, provided there is an improvement of at least 50% if used as an evaluable site of disease
* No prior lymphoma, Hodgkin's lymphoma, myelodysplastic syndromes, or leukemia NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.
PATIENT CHARACTERISTICS:
Age:
* 15 to 65
Performance status:
* Not specified
Life expectancy:
* Not specified
Hematopoietic:
* Not specified
Hepatic:
* Bilirubin no greater than 1.5 times upper limit of normal (ULN)
* No nonlymphoma-related hepatic dysfunction
Renal:
* Creatinine no greater than 2 times ULN
* Creatinine clearance at least 60 mL/min
* No nonlymphoma-related renal dysfunction
* No history of grade 3 hemorrhagic cystitis due to cyclophosphamide
Cardiovascular:
* No coronary artery disease, cardiomyopathy, congestive heart failure, or dysrhythmia requiring therapy
* MUGA scan or 2-D echocardiogram required if patient's history is questionable
* Ejection fraction normal
Pulmonary:
* DLCO or FEV_1 at least 60% of predicted
Other:
* Not pregnant or nursing
* Fertile patients must use effective contraception
* HIV negative
* No other malignancy within the past 5 years except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
* No allergy to etoposide
* No active bacterial, fungal, or viral infection
PRIOR CONCURRENT THERAPY:
Biologic therapy:
* No prior monoclonal antibody therapy for lymphoma except if included in a single course of CHOP/CHOP-R
Chemotherapy:
* No prior chemotherapy for lymphoma except for a single course of CHOP/CHOP-R\* NOTE: \*Prednisone or other corticosteroids not considered prior chemotherapy
Endocrine therapy:
* See Chemotherapy
* Prior corticosteroids allowed
Radiotherapy:
* No prior radiotherapy for lymphoma
* No prior thoracic radiotherapy or radiotherapy greater than 2,000 cGy to any other site
Surgery:
* Not specified
Gender
All
Gender Based
false
Keywords
stage III grade 3 follicular lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage III adult diffuse large cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage III adult Burkitt lymphoma
stage IV grade 3 follicular lymphoma
stage IV adult diffuse small cleaved cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult immunoblastic large cell lymphoma
stage IV adult Burkitt lymphoma
contiguous stage II grade 3 follicular lymphoma
contiguous stage II adult diffuse small cleaved cell lymphoma
contiguous stage II adult diffuse mixed cell lymphoma
contiguous stage II adult immunoblastic large cell lymphoma
contiguous stage II adult diffuse large cell lymphoma
contiguous stage II adult Burkitt lymphoma
noncontiguous stage II grade 3 follicular lymphoma
noncontiguous stage II adult diffuse small cleaved cell lymphoma
noncontiguous stage II adult diffuse mixed cell lymphoma
noncontiguous stage II adult immunoblastic large cell lymphoma
noncontiguous stage II adult diffuse large cell lymphoma
noncontiguous stage II adult Burkitt lymphoma
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
65 Years
Minimum Age
15 Years
NCT Id
NCT00004031
Org Class
Network
Org Full Name
SWOG Cancer Research Network
Org Study Id
CDR0000065658
Overall Status
Completed
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
SWOG-9704 A Randomized Phase III Trial Comparing Early High Dose Chemoradiotherapy and an Autologous Stem Cell Transplant to Conventional Dose CHOP Chemotherapy Plus Rituximab for CD20+ B Cell Lymphomas (With Possible Late Autologous Stem Cell Transplant) for Patients With Diffuse Aggressive Non-Hodgkin's Lymphoma in the High-Intermediate and High Risk International Classification Prognostic Groups
Primary Outcomes
Outcome Description
Percentage of participants surviving 2 years post registration
Outcome Measure
2-year Overall Survival Rates
Outcome Time Frame
up to 2 years post registration
Outcome Description
Percentage of participants without disease progression up to 2 years post-registration.
Outcome Measure
2 Year Progression-free Survival
Outcome Time Frame
From registration until death
Secondary Ids
Secondary Id
S9704
Secondary Id
U10CA032102
Secondary Outcomes
Outcome Description
Adverse Events (AEs) are reported by CTCAE Version 2.0. Only adverse events that are possibly, probably or definitely related to study drug are reported.
Higher grades indicate higher severity of adverse events.
Higher grades indicate higher severity of adverse events.
Outcome Time Frame
Duration of treatment and follow up until death or 3 years post registration
Outcome Measure
Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs
Start Date
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Child
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
65
Minimum Age Number (converted to Years and rounded down)
15
Investigators
Investigator Type
Principal Investigator
Investigator Name
Joseph Sparano
Investigator Email
jsparano@montefiore.org
Investigator Phone
718-405-8404