Eur J Nucl Med Mol Imaging (2010) 37:1824–1833 DOI 10.1007/s00259-010-1490-5
ORIGINAL ARTICLE
Concordance between four European centres of PET reporting criteria designed for use in multicentre trials in Hodgkin lymphoma Sally F. Barrington & Wendi Qian & Edward J. Somer & Antonella Franceschetto & Bruno Bagni & Eva Brun & Helén Almquist & Annika Loft & Liselotte Højgaard & Massimo Federico & Andrea Gallamini & Paul Smith & Peter Johnson & John Radford & Michael J. O’Doherty
Received: 13 January 2010 / Accepted: 27 April 2010 / Published online: 27 May 2010 # Springer-Verlag 2010
Abstract Purpose To determine if PET reporting criteria for the Response Adapted Treatment in Hodgkin Lymphoma (RATHL) trial could enable satisfactory agreement to be reached between ‘core’ laboratories operating in different countries. Methods Four centres reported scans from 50 patients with stage II–IV HL, acquired before and after two cycles of Adriamycin/bleomycin/vinblastine/dacarbazine. A five-point scale was used to score response scans using ‘normal’ mediastinum and liver as reference levels. Centres read scans independently of each other. The level of agreement between
centres was determined assuming (1) that uptake in sites involved at diagnosis that was higher than liver uptake represented disease (conservative reading), and (2) that uptake in sites involved at diagnosis that was higher than mediastinal uptake represented disease (sensitive reading). Results There was agreement that the response scan was ‘positive’ or ‘negative’ for lymphoma in 44 patients with a conservative reading and in 41 patients with a sensitive reading. Kappa was 0.85 (95% CI 0.74–0.96) for conservative reading and 0.79 (95% CI 0.67–0.90) for sensitive reading. Agreement was reached in 46 and 44 patients after discussion for the conservative and sensitive readings, respectively.
S. F. Barrington (*) : E. J. Somer : M. J. O’Doherty PET Imaging Centre at St Thomas’, Kings College London Division of Imaging, Lambeth Palace Road, London SE1 7EH, UK e-mail:
[email protected]
M. Federico Department of Haematology and Oncology, University of Modena and Reggio Emilia, Modena, Italy
W. Qian MRC Clinical Trials Unit, London, UK
A. Gallamini Hematology Department, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy
A. Franceschetto : B. Bagni Department of Nuclear Medicine, University of Modena and Reggio Emilia, Modena, Italy
P. Smith Cancer Research UK and UCL Cancer Trials Centre, London, UK
E. Brun : H. Almquist Departments of Oncology and Clinical Physiology, Lund University Hospital, Lund, Sweden
P. Johnson Cancer Research UK Clinical Centre, Southampton, UK
A. Loft : L. Højgaard PET and Cyclotron Unit, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
J. Radford The Christie NHS Foundation Trust and the University of Manchester, Manchester, UK
Eur J Nucl Med Mol Imaging (2010) 37:1824–1833
Conclusion The criteria developed for reporting in the RATHL trial are sufficiently robust to be used in a multicentre setting. Keywords Positron emission tomography . Hodgkin lymphoma . Quality control/quality assurance . Clinical trial
Introduction Positron emission tomography (PET) is a powerful prognostic indicator in Hodgkin lymphoma (HL) and aggressive non-Hodgkin lymphoma (NHL) [1]. Recent reports indicate that interim PET performed after two cycles of chemotherapy is a better predictor of response in advanced HL than the International Prognostic Score [2]. The challenge is to determine whether response-adapted therapy using PET can improve patient outcomes. Multicentre trials are underway to test whether PET can be used to safely de-escalate therapy in PET ‘responders’ to reduce toxicity without adversely affecting cure rates and to intensify treatment in PET ‘nonresponders’ to improve survival. One such trial is Response-Adapted Therapy in Hodgkin Lymphoma (RATHL) trial (www.cancer.gov/clinicaltrials, reference NCT00678327). An important aspect of designing multicentre trials involving PET is to ensure that images of high quality are obtained and reported consistently irrespective of the location at which the patient was scanned. Ideally reporting criteria should be flexible enough to allow subgroup analyses of individuals with uptake above background, as ‘minimal residual uptake’ in sites of disease appears to have different implications with regard to patient outcome according to lymphoma type and stage [3, 4] and possibly according to the treatment given. Reporting criteria previously referred to as the ‘London criteria’ [5] have been developed for use in the RATHL trial. The aim of this study was to test in advance of the trial opening whether the criteria would be sufficiently robust to enable satisfactory agreement to be reached between ‘core’ laboratories reading scans in different European countries.
Methods Four European PET centres took part in the reporting exercise. The test dataset was obtained from 50 consecutive patients with HL who had baseline and response PET/CT scans acquired after two cycles of ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) between September 2005 and March 2007 at the St Thomas’ PET Centre, London. Patients who met the eligibility criteria for the RATHL trial (i.e. >18 years of age with stage IIB–IV
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classical HL or stage IIA with adverse features) were identified retrospectively from the patient database held at the PET Centre. All scans were acquired after a 6-h fast on either a Discovery VCT or a Discovery ST camera after administration of 350–400 MBq 18F-fluorodeoxyglucose (FDG). The uptake period of the response scans was always within 10 min of the uptake period of the baseline scans and both scans were acquired on the same camera. Halfbody scans were acquired from the upper thigh to the skull base with separate head and neck views as necessary. Images were reconstructed using OSEM. The CT scans were acquired at 120 kVp and 65 mAs without administration of oral or intravenous contrast agent. Scans were anonymized and saved in DICOM format for loading onto the usual reporting workstation at each centre. Each centre used its standard reporting software (Hermes Medical, GEXeleris or Siemens-Leonardo). Centres B and D used the same reporting software. The scans were reported using a five-point scale. This scale was developed at a meeting held in London attended by invited international PET experts. The presence or absence of uptake above background in regions involved by lymphoma at diagnosis was scored using the mediastinum and the liver as reference organs (Table 1). Reporters were not ‘trained’ in advance of this exercise which was performed prior to the opening of the RATHL trial to determine if the reporting system would be reproducible across national core laboratories undertaking central review. Scans were read by two experienced reporters at each PET centre. The reviewers at each centre scored the scans without knowledge of the clinical history or patient outcome and independently from the other centres taking part. The scores of this ‘independent read’ were collated. Scans where there was disagreement were discussed to determine if consensus could be reached. The hypothesis of the RATHL trial is that FDG PET imaging can be reproducibly and effectively applied in the early assessment of response to chemotherapy for a riskadapted treatment strategy in advanced HL. The design of the RATHL trial is shown in Fig. 1. The study aims to assess: 1. Whether ABVD and AVD produce equivalent outcomes in patients with good prognosis who become PET-negative after two cycles. 2. The 2-year progression-free survival (PFS) in patients who remain PET-positive after two cycles of ABVD and have escalation of chemotherapy to BEACOPP-14 or escalated BEACOPP. Based on 1,200 patients entering the study and a 75% response rate with PET, the study will exclude 3-year PFS being 3–4% worse with AVD than ABVD with 90% power (assuming 3-year PFS with ABVD is 95%). With a total of
1826 Table 1 Five-point scoring system developed for the RATHL trial Note: If mediastinal blood pool activity is equal to or greater than activity in the liver, then the uptake within the lesion should be compared with that in the liver (uptake lesion < liver score 2; lesion = liver score 3)
Eur J Nucl Med Mol Imaging (2010) 37:1824–1833 Score
PET/CT scan result
1 2 3 4 5 X
No uptake above background Uptake ≤ mediastinum Uptake > mediastinum but ≤ liver Uptake moderately increased compared to the liver at any site Uptake markedly increased compared to the liver at any site New areas of uptake unlikely to be related to lymphoma
300 patients receiving intensified chemotherapy, the 2-year PFS in this group of patients would be reliably estimated with a standard error of
