Vienna, Austria

ESTRO 2023

Session Item

May 14
10:30 - 11:30
Hall A
Haematology - CNS
Giuseppe Minniti, Italy;
Lena Specht, Denmark
Proffered Papers
10:30 - 10:40
Mature outcomes for TROG 99.03: RCT of RT +/- (R)-CVP in Stage I-II Follicular Lymphoma
Michael MacManus, Australia


Mature outcomes for TROG 99.03: RCT of RT +/- (R)-CVP in Stage I-II Follicular Lymphoma

Michael MacManus1, John Seymour2, Daniel Roos3, Peter O'Brien4, Andrew Macann5, Richard Tsang6, Sidney Davis7, Sudi Shrestha1, David Joseph8, Maher Gandhi9, Joshua Tobin10

1Peter MacCallum Cancer Centre, Radiation Oncology, Melbourne, Australia; 2Peter MacCallum Cancer Centre, Haematology, Melbourne, Australia; 3Royal Adelaide Hospital, Radiation Oncology , Adelaide, Australia; 4Genesis Care, Radiation Oncology, Newcastle, Australia; 5Auckland City Hospital, Radiation Oncology, Auckland, New Zealand; 6Princess Margaret Hospital, Radiation Oncology, Toronto, Canada; 7Alfred Hospital, Radiation Oncology, Melbourne, Australia; 8Sir Charles Gairdner Hospital, Radiation Oncology, Perth, Australia; 9Princess Alexandra Hospital, Haematology, Brisbane, Australia; 10Mater Hospital, Haematology, Brisbane, Australia

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Purpose or Objective

To present mature data on overall survival (OS), progression free survival (PFS), transformation to aggressive lymphoma and preliminary translational research on biospecimens for the TROG 99.03 international randomised trial of radiotherapy vs radiotherapy plus systemic therapy in stage I-II Follicular Lymphoma (FL). This report adds 2 years additional follow up, new analyses and initial translational research results from trial biospecimens.

Material and Methods

Patients with stage I-II FL, grade 1-3a, staged with CT and bone marrow biopsies +/- FDG-PET were randomized to either; Arm A: 30Gy IFRT alone or Arm B: IFRT followed by 6 cycles of cyclophosphamide 1000 mg/m2 IV D1, vincristine 1.4 mg/m2 D1 and prednisolone 50mg/m2 D1-5 (CVP). From 2006 Rituximab 375 mg/m2 D1 was added to arm B (R-CVP). PET staging gradually became widely adopted. Stored trial biospecimens were analysed for potential prognostic factors, including plasma beta 2 microglobulin (B2M) and gene expression in FFPE tumour biopsies, assessed by nanostring analysis.


From February 2000 to July 2012, 150 patients were, recruited: 75 to arm A (IFRT) and 75 to arm B (44 CVP and 31 R-CVP). Median age was 57, 75% had stage 1 and 48% were PET-staged. At the trial close out date, (median potential follow-up 11.3 years), PFS remained significantly superior for arm B (IFRT + systemic therapy) compared to arm A (HR 0.6 (0.37-0.98); p=0.043). 10 years PFS was 62% for arm B and 43% for arm A. 10 year OS was 95.3 and 84% respectively for arms A and B (HR 0.44, p=0.10). Patients treated with R-CVP had substantially superior PFS compared to those who received IFRT or CVP (81% vs 52% at 8 years, P=0.013, figure 1). When analysis of PFS was confined to 72 PET-staged patients the difference between arms A and B increased (HR 0.35 p=0.027, Figure 2), whereas analysis confined to 78 non-PET staged patients showed no significant difference between arms (HR 0.8, p=0.42).  More than twice as many deaths (13 vs 6) and transformations to aggressive lymphoma (11 vs 5) occurred in Arm A than Arm B. By last follow-up 16 patients had experienced transformation with 11 and 5 cases detected in arms A and B respectively. The HR for either histological transformation or death was 4.0 (p=0.045), consistent with a favourable change in natural history with systemic therapy. Emphasizing the importance of the cytotoxic CD8+ T-cell response, both elevated plasma B2M (HR 2.27, p=0.044) and low intratumoural CD8A gene expression (HR 2.21, p=0.0042) were associated with inferior PFS.


Systemic therapy, especially with rituximab, increased progression free survival and significantly reduced the risk of death or transformation to aggressive lymphoma in stage I-II FL. Most benefit was seen in PET staged patients.  Elevated B2M and lower gene expression associated with anti-tumour immunity were associated with worse outcomes.