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.

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.

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.