Elsevier

The Lancet Haematology

Volume 1, Issue 1, October 2014, Pages e17-e27
The Lancet Haematology

Articles
Prognostic value of PET-CT after first-line therapy in patients with follicular lymphoma: a pooled analysis of central scan review in three multicentre studies

https://doi.org/10.1016/S2352-3026(14)70008-0Get rights and content

Summary

Background

The value of 18F-fluorodeoxyglucose (FDG) PET-CT (PET) imaging in response assessment after first-line rituximab chemotherapy for follicular lymphoma has been documented. We analysed the application of the five-point Deauville scale (5PS; used to score FDG uptake on PET images) in a large cohort derived from three studies, to assess the correlation between post-induction PET status and survival in patients with follicular lymphoma.

Methods

In this pooled analysis, we used data from three multicentre prospective studies of first-line rituximab chemotherapy for patients with high-tumour-burden follicular lymphoma (the PRIMA study, the PET-Folliculaire study, and the Fondazione Italiana Linfomi FOLL05 study). Patients included in this analysis received at least six cycles of rituximab and chemotherapy before response assessment with conventional contrast-enhanced CT and PET low-dose CT (PET). We included only patients who had a PET scan within 3 months of the last dose of induction rituximab. Patient data, including conventional CT-based response assessment, were recorded for all patients undergoing PET review. Scans undergoing central PET review were scored independently by three reviewers according to the 5PS. The primary endpoints were progression-free survival and overall survival according to the 5PS score of post-induction PET scan (ie, positive [≥4 points] or negative [<4 points]), analysed in the central review population.

Findings

Between Dec 24, 2004, and Sept 22, 2010, 439 of the patients enrolled in the three studies underwent local PET assessment, 246 of whom had centrally reviewed post-induction scans. 41 (17%) of 246 patients had a positive post-induction PET scan according to a cutoff of 4 or higher on the 5PS, with substantial reporter concordance. With a median follow-up of 54·8 months (IQR 39·7–68·5; range 7·7–90·1), the hazard ratio (HR) for progression-free survival for patients with a positive PET scan versus those with a negative PET scan was 3·9 (95% CI 2·5–5·9; p<0·0001), and for overall survival was 6·7 (2·4–18·5; p=0·0002). For patients with a positive PET scan, 23·2% (95% CI 11·1–37·9) of patients were progression free at 4 years compared with 63·4% (55·9–70·0) of those who had a negative PET scan (p<0·0001); 4-year overall survival was 87·2% (95% CI 71·9–94·5) versus 97·1% (93·2–98·8), respectively (p<0·0001). Conventional CT-based response (ie, complete response or unconfirmed complete response vs partial response) was weakly predictive of progression-free survival (HR 1·7 [95% CI 1·1–2·5]; p=0·017).

Interpretation

PET-CT rather than contrast-enhanced CT scanning should be considered as a new standard for response assessment of follicular lymphoma in clinical practice, and could help guide response-adapted therapy.

Funding

Groupe d'Etude des Lymphomes de l'Adulte (Paris, France), now LYSA (Lymphoma Study Association), Direction de la Recherche Clinique de l'Assistance Publique–Hôpitaux de Paris, Fondazione Italiana Linfomi, and the Italian Ministry of Health.

Introduction

Follicular lymphoma is a highly prevalent lymphoma with heterogeneous clinical behaviour. Initially sensitive to rituximab chemotherapy, it is characterised by recurrent relapses and risk of histological transformation. Although traditionally thought to be incurable, the longer remissions and extended survival of most patients in the modern therapeutic era challenges this notion, since the median age at diagnosis is 63 years.1, 2 Many patients can now expect to die from other causes while in remission, or with asymptomatic disease. Nonetheless, with substantial variability in the clinical course of follicular lymphoma, patients with a particularly poor outlook are not easily identifiable by either pretreatment prognostic indices (eg, the Follicular Lymphoma International Prognostic Index [FLIPI]3 and FLIPI24), or conventional response assessment with the 1999 International Workshop Criteria (IWC) to standardise response for non-Hodgkin lymphoma.5 Assessment with the IWC involves complex calculations on contrast-enhanced CT of lymph-node dimensions to distinguish complete response, unconfirmed complete response, and partial response from stable or progressive disease, and formal response classification is often not done in routine clinical practice.

PET-CT (PET) with 18F-fluorodeoxyglucose (FDG) after induction therapy is a powerful prognostic imaging method in Hodgkin's and diffuse large B-cell lymphoma. It has been shown to be better than the IWC criteria for the categorisation of response and prognosis and has been recommended since the 2007 International Harmonization Project (IHP) revised criteria for response assessment of these lymphoma types.6, 7 However, the IHP criteria precluded use of PET for response assessment of follicular lymphoma outside the research setting.6, 7

Three prospective cooperative group studies8, 9, 10 of first-line therapy for patients with high-tumour-burden follicular lymphoma showed that FDG uptake is a universal characteristic of follicular lymphoma and therefore emphasised the value of PET in staging and response assessment. In two of these studies,8, 9 a score of 4 points or higher on the recently recommended five-point scale (5PS, also known as the Deauville criteria; panel 1),11 applied during the central review of PET images, was strongly predictive of progression-free survival,9, 12 providing evidence to support the application of the 5PS to response assessment in follicular lymphoma, as now recommended in the 2014 Lugano Classification13 and International Conference on Malignant Lymphoma (ICML) Imaging Working Group consensus guidelines14 for response assessment of FDG-avid lymphomas.

We assessed the independent application of the 5PS to a large cohort derived from these studies8, 9, 10 to provide a more precise correlation between PET status after induction therapy and survival. The objective of this pooled analysis was to confirm the primary role of PET response assessment in follicular lymphoma.

Section snippets

Study design and participants

In this pooled analysis, we used data from three multicentre prospective studies: the two Lymphoma Study Association (formerly Groupe d'Etudes des Lymphomes de l'Adulte) studies—the PRIMA (Primary Rituximab and Maintenance) study15 of rituximab with cyclophosphamide, vincristine, and prednisolone (R-CVP) or cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) and the PET-Folliculaire (PET-FL) study9 of PET assessment during and after rituximab plus CHOP (R-CHOP)—and the

Results

439 patients with post-induction PET scans were enrolled in the three studies between Dec 24, 2004, and Sept 22, 2010: 122 in PRIMA, 112 in the PET-FL, and 205 in the FOLL05 study. Only 85 patients' scans from PRIMA and 121 patients' scans from FOLL05 were submitted for central review, and of those submitted scans several were excluded because PET or CT data were incomplete or not in DICOM format, with scans from 61 (72%) of 85 patients in PRIMA and 79 (65%) of 121 patients in FOLL05 of

Discussion

Increasingly effective therapy for follicular lymphoma now challenges assumptions of the incurable nature of this indolent lymphoma,20 because most patients can now expect extended survival after first-line immunochemotherapy. However, the poor discriminatory capacity of the 1999 IWC contrast-enhanced CT-based response assessment consigns most responding patients (with an unconfirmed complete response or partial response) to an uncertain remission in which only close clinical follow-up

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