PET-CT for staging and early response: results from the Response-Adapted Therapy in Advanced Hodgkin Lymphoma study

Abstract

Key Points• PET-CT is the modern standard for staging Hodgkin lymphoma and can replace contrast enhanced CT in the vast majority of cases.• Agreement between expert and local readers is sufficient for the Deauville criteria to assess response in clinical trials and the community.International guidelines recommend that positron emission tomography-computed tomography (PET-CT) should replace CT in Hodgkin lymphoma (HL). The aims of this study were to compare PET-CT with CT for staging and measure agreement between expert and local readers, using a 5-point scale (Deauville criteria), to adapt treatment in a clinical trial: Response-Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL). Patients were staged using clinical assessment, CT, and bone marrow biopsy (RATHL stage). PET-CT was performed at baseline (PET0) and after 2 chemotherapy cycles (PET2) in a response-adapted design. PET-CT was reported centrally by experts at 5 national core laboratories. Local readers optionally scored PET2 scans. The RATHL and PET-CT stages were compared. Agreement among experts and between expert and local readers was measured. RATHL and PET0 stage were concordant in 938 (80%) patients. PET-CT upstaged 159 (14%) and downstaged 74 (6%) patients. Upstaging by extranodal disease in bone marrow (92), lung (11), or multiple sites (12) on PET-CT accounted for most discrepancies. Follow-up of discrepant findings confirmed the PET characterization of lesions in the vast majority. Five patients were upstaged by marrow biopsy and 7 by contrast-enhanced CT in the bowel and/or liver or spleen. PET2 agreement among experts (140 scans) with a k (95% confidence interval) of 0.84 (0.76-0.91) was very good and between experts and local readers (300 scans) at 0.77 (0.68-0.86) was good. These results confirm PET-CT as the modern standard for staging HL and that response assessment using Deauville criteria is robust, enabling translation of RATHL results into clinical practice. (Blood. 2016;127(12):1531-1538

FDG-PET as a biomarker for early response in diffuse large B-cell lymphoma as well as in Hodgkin lymphoma? Ready for implementation in clinical practice?

“…The liver is a more reliable threshold for reporting iPET with respect to inter-reporter agreement and there was good agreement amongst reporters in local PET centers with expert central reviewers in RATHL. 4 This supports the use of DS 3 for assessment of CMR in patients undergoing standard treatment but, in the authors' opinion, in early stage disease for deescalation it is still prudent to use DS2. It is imperative that those reporting PET results and clinicians understand how the DS should be used for response-adaptation in clinical practice.…”

“…[2][3][4] No FDG uptake is graded as DS 1; uptake less than or equal in intensity to the mediastinum as DS 2; lesions with FDG uptake between mediastinum and liver are assessed as DS 3; uptake more intense than liver is scored as DS 4; and markedly increased uptake or new lymphoma-related lesions as DS 5 ( Figure 1). This categorization has a high interobserver agreement in HL and DLBCL.…”

Advanced Hodgkin’s lymphoma: End-of-treatment FDG-PET should be maintained

“…It offers better initial staging and risk stratification [3]. FDG-PET often detects occult extranodal disease, notably focal bone marrow lesions [5][6][7]. It rendered useless routine bone marrow biopsy [3].…”

PET-guided clinical trials in Hodgkin lymphoma: to agree or not to agree, that is the reviewer’s question

“…In the RATHL study, for example, out of 51 patients scored 4 by local investigator, only 34 (66%) were reclassified as score 4 in the central core laboratory of the study by consensus review [14]. Another aspect impacting reviewer concordance is the availability of a set of practical instruction for a stepwise method to proceed on the review and to exclude from the analysis the most common sources of false-positive results [15].…”

“…In the RATHL trial a network of national core laboratories in the United Kingdom, Italy, Sweden, Denmark, and Australia reported the PET scan images using DS, adopting a mixed independent and consensus review. Two readers at each local core lab, unaware of the patient's clinical status, scored independently the scans and disagreement was resolved by consensus reading, and, in the rare case of persisting disagreement, a third doctor from another core lab adjudicated the scan result [9,13,14]. A similar approach has been successfully adopted by the US Alliance group in the S0816 trial [10], where PET/CT scans were submitted for central review to the CALGB (Cancer and Leukemia Group B) imaging core lab.…”