Positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG) is not as well established for use in follicular lymphoma (FL) as it is for Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL). The likely reason is that the clinical benefit of functional imaging is less well defined in FL, which is often an incurable, remitting, and relapsing condition for which treatment is aimed at disease control and prolonging survival.

FL is almost always FDG avid.13 In one study, FDG uptake was seen in all but seven of 140 patients (5%), and disease was limited to the bone marrow or the skin.4 PET could therefore be a useful tool to stage FL. This might be particularly important in the distinction between early-stage localized disease, which is potentially curable with involved-field radiotherapy (IFRT),5 and advanced disease, which is incurable and treated with chemotherapy. Several retrospective studies have indicated that PET detects more lesions than computed tomography (CT),68 with a potential to alter management through upstaging or changing the size of the radiotherapy field. Management changes were indicated because of additional disease findings on PET in 18% to 29% of patients with FL6,7; this increased to 45% to 50% when only patients with limited-stage disease as determined by CT were considered.1,8 This suggests that there might be a rationale for using PET for imaging of patients with limited-stage disease to avoid futile IFRT. The outcome of IFRT for localized FL staged by PET has not yet been reported; therefore, it is not known whether the improved staging accuracy will result in improved outcome.

Indolent lymphomas tend to have lower uptake than aggressive lymphomas.9 One study showed that using receiver operating characteristic analysis, an optimal threshold for the standardized uptake value (SUV) of 10 allowed aggressive lymphomas to be distinguished from indolent lymphomas in 69 patients who underwent biopsy with sensitivity and specificity of 71% and 81%, respectively.9 Higher uptake has also been observed in patients with indolent lymphomas who undergo transformation.7,10 Thus, there may be a rationale for using PET to identify the most appropriate site for biopsy in patients with FL at diagnosis and with suspected transformation.

More recently, interest has turned to the role of PET in response assessment after chemotherapy8,11,12 and radioimmunotherapy.13,14 Reports suggested that patients with PET-positive scans had worse outcomes than patients with PET-negative scans in untreated8,11,13 and relapsed/refractory disease.11,14 These studies, however, involved heterogeneous groups with respect to stage, treatment,6,8,11,12 and the timing of PET scans.8

Last year, Journal of Clinical Oncology published a study that reported the results of postinduction PET-CT scans in 122 patients with FL who were enrolled onto the Primary Rituximab and Maintenance (PRIMA) trial.15 Patients were treated with rituximab plus six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or rituximab plus eight cycles of cyclophosphamide, vincristine, and prednisone (R-CVP) and randomly assigned to observation or 2 years of maintenance rituximab. Patients with PET-positive scans after induction had significantly worse outcomes than patients with PET-negative scans. Progression-free survival (PFS) rates were 32.9% and 70.7% (P < .001), and overall survival (OS) rates were 78.5% and 96.5% (P = .0011) for patients with PET-positive and PET-negative scans, respectively, with a median follow-up of 42 months. There was a significant difference in PFS for patients according to PET status in the observation but not in the maintenance arm, probably because of better outcomes and inadequate patient numbers in the maintenance arm.

PET-based response assessment was more predictive than conventional response assessment using international working criteria (IWC). In the multivariate Cox analyses, both PET-based and IWC-based responses were significant, but the IWC was only significant for progressive disease or stable disease (7% of patients) versus the remainder of the study patients. Within the IWC-defined responders (93%), PET was positive in 38% of patients with partial response and 18% of patients with complete response or complete response unconfirmed. The study was limited by its retrospective nature and the PET methodology. The PET-CT result was the interpretation by the local investigator of an imaging report that did not make reference to standardized criteria for PET reporting, which had not been developed at that time. Reports were given by more than 40 physicians, and acquisition parameters for PET were not specified. Despite these drawbacks, the study15 presented the first evidence that PET-CT might be a useful therapeutic end point in FL and identified a cohort of patients with less favorable outcome treated in a clinical trial.

There have been significant efforts since to develop standardized methods for PET acquisition and interpretation for use in clinical trials and best clinical practice.1619 In the article that accompanies this editorial, Dupuis et al20 report a prospective study involving 121 patients with high–tumor burden FL that was defined on the basis of bulk, symptoms, or laboratory abnormalities, as for the PRIMA trial.15 Patients were treated with six cycles of R-CHOP followed by two infusions of rituximab. One hundred eleven patients had interim PET scans after four cycles and 106 patients had end-of-treatment PET scans. The PET methods were set a priori with standardized acquisition and nationally agreed methods for quality control. All scans were analyzed by central review. Three experts used criteria recommended for PET interpretation at the first international workshop on PET in lymphoma held in Deauville, France.19 The Deauville criteria (DC) comprise a simple five-point score in which the level of any residual FDG uptake is compared with uptake in reference sites of normal mediastinum and liver.

The DC with a cutoff of ≥ 4 seem to have worked well both at interim and end-of-treatment assessments. The reviewers had high levels of agreement, as has been previously reported in HL using DC.16,21 Agreement was better using the liver than the mediastinum as the reference site to define a PET-positive result. Both interim and end-of-treatment scans were predictive of 2-year PFS, with rates of 61% versus 86% (P = .0046) and 51% versus 87% (P < .001) for interim and end-of-treatment positive and negative scans, respectively, with a median follow-up of 23 months. End-of-treatment but not interim scans were predictive of 2-year OS with rates of 88% versus 100% (P = .0128) for positive and negative scans. The apparent better performance of PET at the end of treatment may indicate that metabolic response is slow in this indolent lymphoma and is better assessed after adequate treatment. The authors concluded that a scan at the end of treatment was sufficient. The numbers involved are probably too small to assume that changing patterns of FDG uptake during treatment have no prognostic importance, but pragmatically, the optimal time to intervene in FL to improve outcomes is likely to be at the end of induction treatment, which differs from HL and DLBCL, in which interest has focused on interim scanning.

When PET was compared with other prognostic factors, Follicular Lymphoma International Prognostic Index score was not predictive of PFS or OS, but PET remained predictive of survival across Follicular Lymphoma International Prognostic Index risk groups. Dupuis et al20 should be congratulated for providing prospective evidence that PET is a reliable response assessment tool in patients with FL receiving first-line treatment with immunochemotherapy and for providing direction as to how and when PET scans might be used in this setting. A frequent deficiency in the evaluation of imaging for the assessment of disease response has been for individual groups to “do it their way,” leading to difficulties formulating common methods for use in clinical trials and everyday practice. Following initiatives in HL and DLBCL to standardize PET methods,17,19,22,23 Dupuis et al have outlined a blueprint for the use of PET in FL for response assessment. The authors have not reported quantitative results for PET as they did previously in DLBCL,2426 and these analyses would be interesting if it is possible to report them.

To what purpose should this new tool for response assessment now be applied in FL? Both the studies by Trotman et al15 and Dupuis et al20 have shown that PET at the end of induction chemotherapy improves the accuracy of response assessment compared with conventional IWC alone and that PET-assessed response is better in predicting PFS and possibly OS. The question therefore is whether these two studies provide enough evidence to extend the revised IWC (including PET)18 to FL. The answer is probably a reserved “Yes.” These two studies were limited to patients with high tumor burdens. Although this group is the most likely to be treated and require response assessment, there are currently no data on the remainder of patients with FL. R-CHOP was the primary treatment used (for 84% of patients in the study by Trotman et al15 and for 100% of patients in the study by Dupuis et al20). The effect of maintenance on the prognostic value of end-of-treatment PET needs further clarification. The study by Dupuis et al did not involve maintenance therapy, and the study by Trotman et al had insufficient power to show a difference in PFS according to PET in patients receiving maintenance therapy. Despite these caveats, the evidence is growing for the inclusion of FDG-PET in response evaluation of FL, and its potential role in response-guided treatment and evaluation of novel agents needs to be investigated.

© 2012 by American Society of Clinical Oncology

See accompanying article on page 4317

The author(s) indicated no potential conflicts of interest.

Manuscript writing: All authors

Final approval of manuscript: All authors

1. A Wirth, M Foo, JF Seymour, etal: Impact of [18f] fluorodeoxyglucose positron emission tomography on staging and management of early-stage follicular non-Hodgkin lymphoma Int J Radiat Oncol Biol Phys 71: 213219,2008 Crossref, MedlineGoogle Scholar
2. R Elstrom, L Guan, G Baker, etal: Utility of FDG-PET scanning in lymphoma by WHO classification Blood 101: 38753876,2003 Crossref, MedlineGoogle Scholar
3. N Tsukamoto, M Kojima, M Hasegawa, etal: The usefulness of (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) and a comparison of (18)F-FDG-PET with (67)gallium scintigraphy in the evaluation of lymphoma: Relation to histologic subtypes based on the World Health Organization classification Cancer 110: 652659,2007 MedlineGoogle Scholar
4. M Weiler-Sagie, O Bushelev, R Epelbaum, etal: (18)F-FDG avidity in lymphoma readdressed: A study of 766 patients J Nucl Med 51: 2530,2010 Crossref, MedlineGoogle Scholar
5. BA Campbell, N Voss, R Woods, etal: Long-term outcomes for patients with limited stage follicular lymphoma: Involved regional radiotherapy versus involved node radiotherapy Cancer 116: 37973806,2010 Crossref, MedlineGoogle Scholar
6. A Janikova, K Bolcak, T Pavlik, etal: Value of [18F]fluorodeoxyglucose positron emission tomography in the management of follicular lymphoma: The end of a dilemma? Clin Lymphoma Myeloma 8: 287293,2008 Crossref, MedlineGoogle Scholar
7. M Karam, L Novak, J Cyriac, etal: Role of fluorine-18 fluoro-deoxyglucose positron emission tomography scan in the evaluation and follow-up of patients with low-grade lymphomas Cancer 107: 175183,2006 Crossref, MedlineGoogle Scholar
8. L Le Dortz, S De Guibert, S Bayat, etal: Diagnostic and prognostic impact of 18F-FDG PET/CT in follicular lymphoma Eur J Nucl Med Mol Imaging 37: 23072314,2010 Crossref, MedlineGoogle Scholar
9. H Schöder, A Noy, M Gönen, etal: Intensity of 18fluorodeoxyglucose uptake in positron emission tomography distinguishes between indolent and aggressive non-Hodgkin's lymphoma J Clin Oncol 23: 46434651,2005 LinkGoogle Scholar
10. A Noy, H Schöder, M Gönen, etal: The majority of transformed lymphomas have high standardized uptake values (SUVs) on positron emission tomography (PET) scanning similar to diffuse large B-cell lymphoma (DLBCL) Ann Oncol 20: 508512,2009 Crossref, MedlineGoogle Scholar
11. S Bishu, JM Quigley, SR Bishu, etal: Predictive value and diagnostic accuracy of F-18-fluoro-deoxy-glucose positron emission tomography treated grade 1 and 2 follicular lymphoma Leuk Lymphoma 48: 15481555,2007 Crossref, MedlineGoogle Scholar
12. PL Zinzani, G Musuraca, L Alinari, etal: Predictive role of positron emission tomography in the outcome of patients with follicular lymphoma Clin Lymphoma Myeloma 7: 291295,2007 Crossref, MedlineGoogle Scholar
13. SA Jacobs, SH Swerdlow, J Kant, etal: Phase II trial of short-course CHOP-R followed by 90Y-ibritumomab tiuxetan and extended rituximab in previously untreated follicular lymphoma Clin Cancer Res 14: 70887094,2008 Crossref, MedlineGoogle Scholar
14. E Lopci, L Zanoni, A Chiti, etal: FDG PET/CT predictive role in follicular lymphoma Eur J Nucl Med Mol Imaging 39: 864871,2012 Crossref, MedlineGoogle Scholar
15. J Trotman, M Fournier, T Lamy, etal: Positron emission tomography-computed tomography (PET-CT) after induction therapy is highly predictive of patient outcome in follicular lymphoma: Analysis of PET-CT in a subset of PRIMA trial participants J Clin Oncol 29: 31943200,2011 LinkGoogle Scholar
16. SF Barrington, W Qian, EJ Somer, etal: Concordance between four European centres of PET reporting criteria designed for use in multicentre trials in Hodgkin lymphoma Eur J Nucl Med Mol Imaging 37: 18241833,2010 Crossref, MedlineGoogle Scholar
17. R Boellaard, MJ O'Doherty, WA Weber, etal: FDG PET and PET/CT: EANM procedure guidelines for tumour PET imaging—Version 1.0 Eur J Nucl Med Mol Imaging 37: 181200,2010 Crossref, MedlineGoogle Scholar
18. BD Cheson, B Pfistner, ME Juweid, etal: Revised response criteria for malignant lymphoma J Clin Oncol 25: 579586,2007 LinkGoogle Scholar
19. M Meignan, A Gallamini, M Meignan, etal: Report on the First International Workshop on Interim-PET-Scan in Lymphoma Leuk Lymphoma 50: 12571260,2009 Crossref, MedlineGoogle Scholar
20. J Dupuis, A Berriolo-Riedinger, A Julian, etal: Impact of [18F]fluorodeoxyglucose positron emission tomography response evaluation in patients with high–tumor burden follicular lymphoma treated with immunochemotherapy: A prospective study from the Groupe d'Etudes des Lymphomes de l'Adulte and GOELAMS J Clin Oncol 30: 43174322,2012 LinkGoogle Scholar
21. C Furth, H Amthauer, H Hautzel, etal: Evaluation of interim PET response criteria in paediatric Hodgkin's lymphoma: Results for dedicated assessment criteria in a blinded dual-centre read Ann Oncol 22: 11981203,2011 Crossref, MedlineGoogle Scholar
22. R Boellaard, WJ Oyen, CJ Hoekstra, etal: The Netherlands protocol for standardisation and quantification of FDG whole body PET studies in multi-centre trials Eur J Nucl Med Mol Imaging 35: 23202333,2008 Crossref, MedlineGoogle Scholar
23. SF Barrington, JE Mackewn, P Schleyer, etal: Establishment of a UK-wide network to facilitate the acquisition of quality assured FDG-PET data for clinical trials in lymphoma Ann Oncol 22: 739745,2011 Crossref, MedlineGoogle Scholar
24. RO Casasnovas, M Meignan, A Berriolo-Riedinger, etal: SUVmax reduction improves early prognosis value of interim positron emission tomography scans in diffuse large B-cell lymphoma Blood 118: 3743,2011 Crossref, MedlineGoogle Scholar
25. E Itti, C Lin, J Dupuis, etal: Prognostic value of interim 18F-FDG PET in patients with diffuse large B-Cell lymphoma: SUV-based assessment at 4 cycles of chemotherapy J Nucl Med 50: 527533,2009 Crossref, MedlineGoogle Scholar
26. C Lin, E Itti, C Haioun, etal: Early 18F-FDG PET for prediction of prognosis in patients with diffuse large B-cell lymphoma: SUV-based assessment versus visual analysis J Nucl Med 48: 16261632,2007 Crossref, MedlineGoogle Scholar

COMPANION ARTICLES

No companion articles

ARTICLE CITATION

DOI: 10.1200/JCO.2012.45.4082 Journal of Clinical Oncology 30, no. 35 (December 10, 2012) 4285-4287.

Published online October 29, 2012.

PMID: 23109690

ASCO Career Center