Radiotherapy Versus Radiotherapy Plus Chemotherapy in Early Stage Follicular Lymphoma

A Randomised Multicentre Trial of Involved Field Radiotherapy Versus Involved Field Radiotherapy Plus Chemotherapy in Combination With Rituximab (Mabthera®) for Stage I - II Low Grade Follicular Lymphoma

Patients with stage I and II low grade follicular lymphoma are randomised between standard therapy (involved field radiotherapy) and investigational therapy (involved field radiotherapy and chemotherapy plus rituximab). The main endpoint is progression free survival but overall survival and the influence of t(14;18) status will also be studied.

Study Overview

• Status: Completed
• Conditions: Follicular Lymphoma
• Intervention / Treatment: Drug: Cyclophosphamide; Radiation: Radiotherapy; Drug: Vincristine; Drug: Prednisolone; Drug: Rituximab

Detailed Description

Radiotherapy is the only modality which has been proven to have curative potential in patients with localised low grade lymphoma. Despite excellent control of the local tumour, most patients relapse outside the area treated with radiation and most of these ultimately die from lymphoma. This study tests the hypothesis that the addition of six cycles of chemotherapy plus rituximab (systemic chemotherapy) can eradicate undetectable lymphoma deposits outside the radiation field and thereby improve the cure rate. The study will specifically test the hypothesis that six cycles of adjuvant CVP chemotherapy (cyclophosphamide, vincristine, prednisolone) in combination with Rituximab will improve progression-free survival for patients with stage I and II low-grade follicular lymphoma treated with involved-field radiotherapy (IFRT). That is, will patients given radiotherapy plus systemic chemotherapy live longer or remain free from disease longer than patients treated with radiation alone? Radiotherapy alone is widely regarded as the standard treatment for this disease.

There are a number of secondary endpoints to the study, as follows:

1. Comparison the pre- and post-treatment prevalence of the t(14:18) translocation, in peripheral blood and bone marrow, of patients treated with either IFRT alone or IFRT plus chemotherapy. This translocation is potentially a marker for minimal residual disease and eradication of the marker from blood cells may have prognostic implications. The clinical value of "molecular remission" as an early predictor of freedom from progression (FFP) and survival will be assessed.
2. Comparison of overall survival and FFP for patients treated with IFRT alone with overall survival and FFP for patients treated with combined IFRT and systemic therapy. Delay of progression of disease may be of limited value if overall survival is the same.
3. Comparison of acute and late toxicity and second malignancy rates for patients treated with IFRT or IFRT plus systemic therapy.
4. Delineation of the location of first relapse in relation to radiation therapy fields.

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Australian Capital Territory
    • Garran, Australian Capital Territory, Australia, 2605
      • The Canberra Hospital
  • New South Wales
    • Newcastle, New South Wales, Australia, 2298
      • Calvary Mater Newcastle
    • Randwick, New South Wales, Australia, 2031
      • Prince of Wales Hospital
    • Wentworthville, New South Wales, Australia, 2145
      • Westmead Hospital
    • West Albury, New South Wales, Australia, 2640
      • Albury Base/Murray Valley Private Hospital
    • Wollongong, New South Wales, Australia, 2500
      • Illawarra Cancer Care Centre
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
      • Radiation Oncology - Mater Centre
    • Tugun, Queensland, Australia, 4224
      • Genesis Cancer Care (previously Premion)
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
    • Woodville, South Australia, Australia, 5011
      • The Queen Elizabeth Hospital
  • Tasmania
    • Launceston, Tasmania, Australia, 7250
      • Launceston General Hospital
  • Victoria
    • Ballarat, Victoria, Australia, 3350
      • St John of God Hospital
    • East Melbourne, Victoria, Australia, 3002
      • Peter Maccallum Cancer Centre
    • Geelong, Victoria, Australia, 3220
      • Andrew Love Cancer Care Centre, Geelong Hospital
    • Heidelberg, Victoria, Australia, 3084
      • Austin Health
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Sir Charles Gairdner Hospital
• Canada
  • Toronto, Canada
    • Princess Margaret Hospital
• New Zealand
  • Auckland, New Zealand, 1001
    • Auckland Hospital
  • Hamilton, New Zealand, 3200
    • Waikato Hospital
  • Wellington, New Zealand, 7902
    • Wellington Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult patients (≥ 18 years old) with histologically documented "follicular lymphoma, grade 1", grade 2", or "follicular lymphoma, grade 3a" diagnosed following an excisional, incisional or generous core biopsy. (i.e. an FNA alone is insufficient.)
• Disease limited to stages I and II after adequate staging
• Anticipated life expectancy > 5 years
• Given written informed consent
• Been assessed by a radiation oncologist and a medical oncologist/ haematologist
• WCC > 3.0 x 10^9/L, platelet count > 100 x 10^9/L, serum creatinine < 0.15 mmol/L
• Ability to commence radiotherapy within 6 weeks of randomisation
• Women using effective contraception, are not pregnant and agree not to become pregnant during participating in the trial and during the 12 months thereafter. Men agree not to father a child during participation in the trial and during the 12 months thereafter.

Exclusion Criteria:

• Received previous systemic cytotoxic chemotherapy.
• Received previous radiotherapy, (except superficial radiation therapy for non-melanoma skin cancers).
• Received previous immunotherapy.
• A medical contraindication to radiotherapy, chemotherapy, or rituximab.
• Any previous or concurrent malignancy other than curatively treated non-melanoma skin cancer, level 1 malignant melanoma, or in situ cervical cancer, unless disease and treatment-free for 5 years.
• Such extensive involvement of the thorax that treatment with radiation therapy alone would be hazardous because of excessive lung irradiation, even if a shrinking field technique were employed.
• Suspected or confirmed pregnancy. Must not be lactating.
• Patients who have known human immuno-deficiency virus (HIV) infection or active hepatitis B (HBV).
• Treatment within a clinical study within 30 days prior to study entry.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Radiotherapy+ Chemotherapy; Involved field Radiotherapy (RT) 30-36 GY plus Cyclophosphamide, Vincristine and Prednisolone (CVP) + rituximab × 6 cycles	Drug: Cyclophosphamide; 1000 mg/m2 I.V. on day 1; Other Names: Cycloblastin, Endoxan; Radiation: Radiotherapy; The prescribed dose to the target volume will be 30 Gy. Daily fractions of 1.5-2.0 Gy will be employed.; Other Names: Radiation; Drug: Vincristine; 1.4 mg/m2 (maximum single dose of 2 mg) I.V. on day 1; Other Names: Vincristine Sulfate Injection; Drug: Prednisolone; 50 mg/m2 orally daily for days 1 - 5; Other Names: Panafcort, Panafcortelone, Predsone, Predsolone; Drug: Rituximab; 375 mg/m2 IV Infusion day 1; Other Names: Erbitux, Mabthera
ACTIVE_COMPARATOR: Radiotherapy alone; Involved field Radiotherapy (30-36 GY) alone	Radiation: Radiotherapy; The prescribed dose to the target volume will be 30 Gy. Daily fractions of 1.5-2.0 Gy will be employed.; Other Names: Radiation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression Free Survival (PFS). Period from the date of randomisation to 1st progression of disease or death from any cause.	Main analysis after at least 3 years of follow-up following the end of accrual. An updated analysis may be done on completion of 5 years follow-up after the end of accrual. Long term follow-up analysis is planned after 10 years of follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pre- and post-treatment prevalence of the t(14;18) translocation, in peripheral blood and bone marrow between arms		Peripheral blood at commencement of treatment, after 1 year and upon relapse is collected and stored for later analysis to be done as part of translational studies when funding becomes available
Overall Survival (OS)	Period from date of randomisation to date of death from any cause.	Main analysis will be done on completion of 5 years follow-up after the end of accrual. An interim analysis to be done after at least 3 years of follow-up. A futility analysis will be performed after the 5 year analysis. In the absence of futility being
Location of first relapse	Period from date of randomisation to date of first relapse location via CT scan and or other imaging as required	Main analysis after at least 3 years of follow-up following the end of accrual. An updated analysis may be done on completion of 5 years follow-up after the end of accrual
To compare time to evolution to higher histological grade	Period from date of randomisation to date of higher histological grade via CT scan and or other imaging as required	Main analysis after at least 3 years of follow-up following the end of accrual. An updated analysis may be done on completion of 5 years follow-up after the end of accrual
Freedom from progression.	Period from date of randomisation to date of first disease progression.	Main analysis after at least 3 years of follow-up following the end of accrual. An updated analysis may be done on completion of 5 years follow-up after the end of accrual. Long term follow-up analysis is planned after 10 years of follow-up
Acute and late toxicities and secondary malignances		Frame after at least 3 years of follow-up following the end of accrual. An updated analysis may be done on completion of 5 years follow-up after the end of accrual

Collaborators and Investigators

• Sponsor: Trans Tasman Radiation Oncology Group
• Collaborators: Australasian Leukaemia and Lymphoma Group
• Investigators: Study Chair: Michael MacManus, MD, Peter MacCallum Cancer Centre, Australia

Publications and helpful links

General Publications

• MacManus M, Fisher R, Roos D, O'Brien P, Macann A, Davis S, Tsang R, Christie D, McClure B, Joseph D, Jayamohan J, Seymour JF. Randomized Trial of Systemic Therapy After Involved-Field Radiotherapy in Patients With Early-Stage Follicular Lymphoma: TROG 99.03. J Clin Oncol. 2018 Oct 10;36(29):2918-2925. doi: 10.1200/JCO.2018.77.9892. Epub 2018 Jul 5.

Helpful Links

• Click here for more information about this study on the TROG official website

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 1, 2000
• Primary Completion (ACTUAL): August 1, 2018
• Study Completion (ACTUAL): August 1, 2018

Study Registration Dates

• First Submitted: June 23, 2005
• First Submitted That Met QC Criteria: June 23, 2005
• First Posted (ESTIMATE): June 24, 2005

Study Record Updates

• Last Update Posted (ACTUAL): November 18, 2022
• Last Update Submitted That Met QC Criteria: November 16, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Rituximab; Radiotherapy; Chemotherapy; Randomised Trial; Stage I-II low grade follicular lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, Follicular; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; 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; Antineoplastic Agents, Immunological; Prednisolone; Cyclophosphamide; Rituximab; Vincristine
• Other Study ID Numbers: TROG 99.03; ALLG NHLLOW5 (OTHER: Collaborative group)