1. Carlson, Robert H.

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Tumor response to induction therapy is an important marker for clinical benefit in Hodgkin lymphoma and essential for determining appropriate treatment regimen.

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In a recent issue of Blood (2015;127:1531-1538), Barrington and colleagues report positron emission tomography-computed tomography (PET-CT) is the modern standard for staging Hodgkin lymphoma and can replace contrast-enhanced CT (CECT) in the vast majority of cases, based on the large, international RATHL (Response-Adapted Therapy in Advanced Hodgkin Lymphoma) clinical trial.


RATHL used PET-CT for staging and for response monitoring after two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) to guide treatment modification.


"Staging of Hodgkin lymphoma patients in this large prospective study confirms that an important proportion will be staged differently using PET-CT compared with clinical assessment, CT, and bone marrow biopsy," the authors reported. "When discordance occurs in the imaging stage, PET-CT is usually more accurate than CT."


The authors also said agreement between expert and local readers is sufficient for the 5-point Deauville criteria to assess response in clinical trials and the community.


This study is the first to compare PET-CT staging with the established standard of clinical assessment, contrast-enhanced CT, and bone marrow biopsy stage in a large cohort of patients with advanced Hodgkin lymphoma, the authors said.


Upstaging occurred more frequently than downstaging, they reported, with extranodal disease accounting for 74 percent of the upstaged scans, mostly due to an increased sensitivity of PET for detecting bone marrow involvement.


"CT is not optimal at detecting bone marrow disease; there usually needs to be more advanced changes, often with cortical bone destruction, for bone marrow involvement to be visualized on CT," said lead author Sally F. Barrington, MD, Reader and Honorary Consultant in Nuclear Medicine at the PET Imaging Centre, Division of Imaging Sciences and Biomedical Engineering, King's College London, in an email exchange with OT. But she added "PET with FDG (fluorodeoxyglucose) detects altered glucose metabolism in the marrow much earlier before anatomical changes occur."


The RATHL trial registered 1,214 patients from 2008-2012, with 1,171 baseline PET-CT scans available for retroactive staging assessment.


In the first analysis of RATHL, presented at the 2015 International Conference on Malignant Lymphoma, in Lugano, Switzerland, interim PET-CT was successfully used to select treatment intensification or de-escalation in patients with advanced Hodgkin lymphoma. Importantly, de-escalation in patients with a negative interim PET-CT led to decreased pulmonary toxicity when bleomycin was omitted from ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) without jeopardizing progression-free or overall survival.


The new report now shows agreement between RATHL stage (based on clinical assessment, CT, and bone marrow biopsy) and the PET-CT stage in 938 patients (80 percent), with 159 patients (14 percent) upstaged and 74 patients (6 percent) downstaged by PET-CT.


The main reasons for upstaging were detection of extranodal disease, most commonly in bone marrow, and nodal involvement, mostly below the diaphragm.


Reasons for downstaging included enlarged nodes and/or spleen that were not FDG-avid, and extranodal sites with abnormal morphology but no FDG uptake.


Baseline and response scans were compared and the findings were correlated with other imaging to determine the etiology of lesions that accounted for the discrepancy in stage.


"Follow-up of discrepant findings confirmed the PET characterization of lesions in the vast majority, supporting the notion that PET-CT stage is more accurate than CT in the majority of cases," the authors reported. "These results confirm PET-CT as the modern standard for staging Hodgkin lymphoma, and that response assessment using Deauville criteria is robust, enabling translation of RATHL results into clinical practice."


The study's main limitations were that it was not possible for CECT scans to be re-reviewed alongside PET-CT scans, and they could not measure the impact of PET-CT on management, the authors said.


Cost Not An Issue

The high cost of PET-CT is a concern, arising mainly from the difficulty of producing and transporting radiopharmaceuticals.


While this study did not address cost-effectiveness, Barrington was asked whether cost would be a barrier to the wider use of PET-CT in Hodgkin lymphoma treatment.


"I think it's not an issue, as staging scans are necessary for proper evaluation of response, and they improve the accuracy of that response evaluation," Barrington told OT. "The absence of a baseline scan leads to clinical uncertainty in reporting results at response in a significant number of cases."


PET-CT is now recommended as standard for staging and response assessment in International guidelines for FDG-avid lymphomas, Barrington said, citing two consensus reports. (J Clin Oncol 2014;32:3048-58; J Clin Oncol 2014;32:3059-68).


Scans Reviewed Within 72 Hours

In an accompanying commentary, (Blood 2016;127:1521-22), Josee M. Zijlstra, MD, an Internist/Hematologist in the Department of Hematology at VU University Medical Center, Amsterdam, The Netherlands, noted all baseline and interim PET-CT scans in this trial with more than 1,100 patients were centrally reviewed by five core laboratories using the Deauville system.


"Importantly, these interim PET-CT scans were reviewed within 72 hours to guide further treatment," Zijlstra said. "It must be noted that the design of the infrastructure to transfer, assess, and report these baseline and interim PET scans, in a large international trial, is itself a real challenge for which the authors have to be applauded."


Interpretation of interim and end-of-treatment PET scans can be difficult, especially in Hodgkin lymphoma, Zijlstra said, pointing out FDG uptake in mediastinal masses might be difficult to distinguish from thymic uptake, and sarcoid-like reactions might mimic uptake in hilar pulmonary lymph nodes.


"PET-CT seems to be a robust and reliable cornerstone for staging patients with Hodgkin lymphoma, and for evaluation during treatment, with visual assessment using the Deauville 5-point score," Zijlstra concluded.


"The question of whether patients with advanced-stage HL and interim PET positivity will benefit from a switch from ABVD to escalated BEACOPP will be answered in this important RATHL trial," she continued, but "Barrington and colleagues have demonstrated one of the most essential prerequisites for such trials: appropriate and reliable assessment of imaging."


Robert H. Carlson is a contributing writer.