SWOG-9704 Chemoradiotherapy and Peripheral Stem Cell Transplantation Compared With Combination Chemotherapy in Treating Patients With Non-Hodgkin's Lymphoma

NCT ID: NCT00004031

Last Updated: 2021-02-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 397 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 1997-07-31
• Study Completion Date: 2013-10-31

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.

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.

Conditions

Lymphoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

CHOP/CHOP-R x 3

Cyclophosphamide 750 mg/m2 IV Day 1 Doxorubicin 50 mg/m2 IV Day 1 Prednisone 100 mg/day PO Days 1-5 Vincristine 1.4 mg/m2 IV Day 1 Rituximab 375 mg/m2 IV Day 1 This regimen is repeated every 21 days for 8 cycles

Group Type: ACTIVE_COMPARATOR

rituximab

Intervention Type: BIOLOGICAL

375 mg/m2 IV every 21 days

CHOP regimen

Intervention Type: DRUG

cyclophosphamide

Intervention Type: DRUG

doxorubicin hydrochloride

Intervention Type: DRUG

prednisone

Intervention Type: DRUG

vincristine sulfate

Intervention Type: DRUG

bone marrow ablation with stem cell support

Intervention Type: PROCEDURE

CHOP/CHOP-R x 1 + Autologous Stem Cell Transplant

Cyclophosphamide 750 mg/m2 IV Day 1 Doxorubicin 50 mg/m2 IV Day 1 Prednisone 100 mg/day PO Days 1-5 Vincristine 1.4 mg/m2 IV Day 1 Rituximab 375 mg/m2 IV Day 1 This regimen is repeated every 21 days for 6 cycles followed by autologous stem cell transplant.

Group Type: EXPERIMENTAL

rituximab

Intervention Type: BIOLOGICAL

375 mg/m2 IV every 21 days

CHOP regimen

Intervention Type: DRUG

carmustine

Intervention Type: DRUG

cyclophosphamide

Intervention Type: DRUG

doxorubicin hydrochloride

Intervention Type: DRUG

etoposide

Intervention Type: DRUG

prednisone

Intervention Type: DRUG

vincristine sulfate

Intervention Type: DRUG

bone marrow ablation with stem cell support

Intervention Type: PROCEDURE

peripheral blood stem cell transplantation

Intervention Type: PROCEDURE

radiation therapy

Intervention Type: RADIATION

Interventions

rituximab

375 mg/m2 IV every 21 days

Intervention Type: BIOLOGICAL

CHOP regimen

Intervention Type: DRUG

carmustine

Intervention Type: DRUG

cyclophosphamide

Intervention Type: DRUG

doxorubicin hydrochloride

Intervention Type: DRUG

etoposide

Intervention Type: DRUG

prednisone

Intervention Type: DRUG

vincristine sulfate

Intervention Type: DRUG

bone marrow ablation with stem cell support

Intervention Type: PROCEDURE

peripheral blood stem cell transplantation

Intervention Type: PROCEDURE

radiation therapy

Intervention Type: RADIATION

Eligibility Criteria

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

• Minimum Eligible Age: 15 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Cancer and Leukemia Group B

NETWORK

Sponsor Role: collaborator

Eastern Cooperative Oncology Group

NETWORK

Sponsor Role: collaborator

NCIC Clinical Trials Group

NETWORK

Sponsor Role: collaborator

SWOG Cancer Research Network

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Patrick J. Stiff, MD

Role: STUDY_CHAIR

Loyola University

Thomas C. Shea, MD

Role: STUDY_CHAIR

UNC Lineberger Comprehensive Cancer Center

David P. Schenkein, MD

Role: STUDY_CHAIR

Tufts Medical Center Cancer Center

Stephen Couban, MD

Role: STUDY_CHAIR

Cancer Care Nova Scotia

Locations

Oregon Health & Science University

Portland, Oregon, United States

Tom Baker Cancer Centre - Calgary

Calgary, Alberta, Canada

Cross Cancer Institute at University of Alberta

Edmonton, Alberta, Canada

CancerCare Manitoba

Winnipeg, Manitoba, Canada

Moncton Hospital

Moncton, New Brunswick, Canada

Doctor H. Bliss Murphy Cancer Centre

St. John's, Newfoundland and Labrador, Canada

Nova Scotia Cancer Centre

Halifax, Nova Scotia, Canada

Margaret and Charles Juravinski Cancer Centre

Hamilton, Ontario, Canada

London Regional Cancer Program at London Health Sciences Centre

London, Ontario, Canada

Odette Cancer Centre at Sunnybrook

Toronto, Ontario, Canada

Hopital Notre-Dame du CHUM

Montreal, Quebec, Canada

Hopital Du Sacre-Coeur de Montreal

Montreal, Quebec, Canada

Centre Hospitalier Universitaire de Quebec

Québec, Quebec, Canada

Hopital du Saint-Sacrement - Quebec

Québec, Quebec, Canada

Saskatoon Cancer Centre at the University of Saskatchewan

Saskatoon, Saskatchewan, Canada

Countries

United States; Canada

References

Stiff PJ, Unger JM, Cook J, et al.: Randomized phase III U.S./Canadian intergroup trial (SWOG S9704) comparing CHOP ± R for eight cycles to CHOP ± R for six cycles followed by autotransplant for patients with high-intermediate (H-Int) or high IPI grade diffuse aggressive non-Hodgkin lymphoma (NHL). [Abstract] J Clin Oncol 29 (Suppl 15): A-8001, 2011.

Reference Type: RESULT

Cook JR, Goldman B, Tubbs RR, Rimsza L, Leblanc M, Stiff P, Fisher R. Clinical significance of MYC expression and/or "high-grade" morphology in non-Burkitt, diffuse aggressive B-cell lymphomas: a SWOG S9704 correlative study. Am J Surg Pathol. 2014 Apr;38(4):494-501. doi: 10.1097/PAS.0000000000000147.

Reference Type: DERIVED

PMID: 24625415 (View on PubMed)

Stiff PJ, Unger JM, Cook JR, Constine LS, Couban S, Stewart DA, Shea TC, Porcu P, Winter JN, Kahl BS, Miller TP, Tubbs RR, Marcellus D, Friedberg JW, Barton KP, Mills GM, LeBlanc M, Rimsza LM, Forman SJ, Fisher RI. Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. N Engl J Med. 2013 Oct 31;369(18):1681-90. doi: 10.1056/NEJMoa1301077.

Reference Type: DERIVED

PMID: 24171516 (View on PubMed)

Other Identifiers

S9704

Identifier Type: OTHER

Identifier Source: secondary_id

U10CA032102

Identifier Type: NIH

Identifier Source: secondary_id

View Link

CDR0000065658

Identifier Type: -

Identifier Source: org_study_id