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

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

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.

Study Overview

• Status: Completed
• Conditions: Lymphoma
• Intervention / Treatment: Drug: cyclophosphamide; Radiation: radiation therapy; Drug: prednisone; Drug: etoposide; Drug: vincristine sulfate; Drug: doxorubicin hydrochloride; Procedure: peripheral blood stem cell transplantation; Drug: CHOP regimen; Drug: carmustine; Procedure: bone marrow ablation with stem cell support; Biological: rituximab

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.

• Study Type: Interventional
• Enrollment (Actual): 397
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre - Calgary
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute at University of Alberta
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • New Brunswick
    • Moncton, New Brunswick, Canada, E1C 6Z8
      • Moncton Hospital
  • Newfoundland and Labrador
    • St. John's, Newfoundland and Labrador, Canada, AIB 3V6
      • Doctor H. Bliss Murphy Cancer Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
      • Nova Scotia Cancer Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Margaret and Charles Juravinski Cancer Centre
    • London, Ontario, Canada, N6A 4L6
      • London Regional Cancer Program at London Health Sciences Centre
    • Toronto, Ontario, Canada, M4N 3M5
      • Odette Cancer Centre at Sunnybrook
  • Quebec
    • Montreal, Quebec, Canada, H4J 1C5
      • Hopital du Sacre-Coeur de Montreal
    • Montreal, Quebec, Canada, H2L 4M1
      • Hopital Notre-Dame du CHUM
    • Quebec City, Quebec, Canada, G1R 2J6
      • Centre Hospitalier Universitaire de Quebec
    • Quebec City, Quebec, Canada, G1S 4L8
      • Hopital du Saint-Sacrement - Quebec
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 4H4
      • Saskatoon Cancer Centre at the University of Saskatchewan
• United States
  • Oregon
    • Portland, Oregon, United States, 97201
      • Oregon Health & Science University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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	Drug: cyclophosphamide; Drug: prednisone; Drug: vincristine sulfate; Drug: doxorubicin hydrochloride; Drug: CHOP regimen; Procedure: bone marrow ablation with stem cell support; Biological: rituximab; 375 mg/m2 IV every 21 days
Experimental: 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.	Drug: cyclophosphamide; Radiation: radiation therapy; Drug: prednisone; Drug: etoposide; Drug: vincristine sulfate; Drug: doxorubicin hydrochloride; Procedure: peripheral blood stem cell transplantation; Drug: CHOP regimen; Drug: carmustine; Procedure: bone marrow ablation with stem cell support; Biological: rituximab; 375 mg/m2 IV every 21 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
2-year Overall Survival Rates	Percentage of participants surviving 2 years post registration	up to 2 years post registration
2 Year Progression-free Survival	Percentage of participants without disease progression up to 2 years post-registration.	From registration until death

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs	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.	Duration of treatment and follow up until death or 3 years post registration

Collaborators and Investigators

• Sponsor: Southwest Oncology Group
• Collaborators: National Cancer Institute (NCI); Eastern Cooperative Oncology Group; NCIC Clinical Trials Group; Cancer and Leukemia Group B
• Investigators: Study Chair: Patrick J. Stiff, MD, Loyola University; Study Chair: Thomas C. Shea, MD, UNC Lineberger Comprehensive Cancer Center; Study Chair: David P. Schenkein, MD, Tufts Medical Center Cancer Center; Study Chair: Stephen Couban, MD, Cancer Care Nova Scotia

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: July 1, 1997
• Primary Completion (Actual): June 1, 2008
• Study Completion (Actual): October 31, 2013

Study Registration Dates

• First Submitted: December 10, 1999
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Actual): February 2, 2021
• Last Update Submitted That Met QC Criteria: January 29, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: 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 large cell lymphoma; stage IV adult immunoblastic large cell lymphoma; stage IV adult Burkitt lymphoma; stage III grade 3 follicular lymphoma; stage III adult diffuse small cleaved cell lymphoma; stage III adult diffuse mixed cell lymphoma; stage IV adult diffuse small cleaved cell lymphoma; stage IV adult diffuse mixed cell lymphoma; contiguous stage II adult diffuse small cleaved cell lymphoma; noncontiguous stage II adult diffuse small cleaved cell lymphoma; noncontiguous stage II adult diffuse large cell lymphoma; noncontiguous stage II adult diffuse mixed cell lymphoma; noncontiguous stage II grade 3 follicular lymphoma; noncontiguous stage II adult Burkitt lymphoma; noncontiguous stage II adult immunoblastic large cell lymphoma; contiguous stage II adult Burkitt lymphoma; contiguous stage II adult immunoblastic large cell lymphoma; contiguous stage II grade 3 follicular lymphoma; contiguous stage II adult diffuse large cell lymphoma; contiguous stage II adult diffuse mixed cell lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, Non-Hodgkin; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Cyclophosphamide; Etoposide; Rituximab; Prednisone; Doxorubicin; Liposomal doxorubicin; Vincristine; Carmustine
• Other Study ID Numbers: CDR0000065658; U10CA032102 (U.S. NIH Grant/Contract); S9704 (Other Identifier: SWOG)