Lymphoma can be defined as a type of cancer that affects the lymphatic system, namely the lymph nodes, the spleen, the thymus gland, and the bone marrow. Lymphoma is usually divided into two main subtypes: Hodgkin’s Lymphoma (HL), and Non-Hodgkin’s Lymphoma (NHL). Both have numerous additional subtypes, each with different symptoms, treatment strategies and prevalence, with about 90% of lymphoma diagnoses being NHL.
Treatment varies between lymphoma subtypes, and depending on the disease characteristics, treatment may not be effective or tolerated by the patient. To try and fill this gap, new therapies are being developed and tested every day in clinical trials.
Clinical trials need to assess the efficacy of the tested treatment, as well as its safety, which can be done through imaging. The evolution of the different imaging techniques to monitor lymphoma has had an impact on how response to treatment is assessed, and thus on the different assessment guidelines consequently developed.
Before the development and spread of modern imaging techniques in the 1970s, tumor assessment mostly depended on clinical results and physical examinations, which gave unprecise and questionable results. The advent of computed tomography (CT) allowed a more accurate assessment, and towards the end of the 1970s, a handbook was published by WHO to describe the first standardized response assessment criteria, which classified patients into four response groups: complete response (CR), partial response (PR), no response/stable disease (SD), and progressive disease (PD).
It was, however, quite vague, and has been revised and re-interpreted later into more precise guidelines. Moreover, some cancers needed specialized criteria to be more accurate, which was the case with hematological malignancies. In the late 1980s, guidelines for response assessment of HL and some forms of leukemia were developed.
For NHL, no standard guidelines were developed until 1999, when the International Working Criteria, also known as Cheson 1999, were developed. Based on CT imaging, they define anatomic parameters to refer to in order to classify patients into CR, PR, SD and PD, as well as a new response classification of “unconfirmed complete response” (uCR). They define the normal lymph node size and explain how to evaluate the size and aspect of different key organs (i.e., liver, spleen, bone marrow, and lymph nodes).
Cheson 1999 criteria quickly became the standard for the assessment of lymphoma response to treatment and helped in the approval process of numerous treatments. However, they were prone to high levels of intra and inter-reader variations, several points were subject to misinterpretation, notably the application of the uCR response, and the recommendations did not include assessment of extra-nodal disease. Besides, the use of 18F-fluorodeoxyglucose (FDG) Positron-Emission Tomography (PET) imaging emerged and quickly became an important part of diagnostic procedures thanks to its ability to show areas of active metabolism, like tumours, and it allows a better discrimination between healthy tissue, non-malignant masses, necrosis, and malignant tissue.
Cheson 1999 criteria were therefore revised to address these gaps and evolved into Cheson 2007. These new criteria define recommendations for the use of PET imaging, include PET results into the response assessment, revise the response categories to eliminate the uCR response, and update the normal lymph node size definition. They also include guidance on how often PET scans should be acquired to avoid false-positive results caused by therapy-induced inflammation.
Just a few years later, the Deauville 5-point score was developed as a tool to assess visually the 18F-FDG uptake, which mirrors the metabolic activity of the assessed area, compared to a reference activity in the aorta and liver. In most lymphoma cases, if, after treatment, the residual tumour uptake is inferior to that of the healthy liver, then the treated patient achieved a CR.
The revision of the Cheson 2007 criteria incorporated the Deauville score to it, which created the Lugano classification in 2014. It defines guidelines for the assessment of PET and CT imaging, for spleen, liver and bone marrow involvement, and for the application of the Deauville score to estimate response and prognosis. Although mostly PET-based to account for lymphoma’s FDG avidity, it also includes CT-based guidance in case PET imaging is unavailable or when the disease has low 18F-FDG uptake, therefore differentiating between metabolic response observed on PET and anatomic response observed on CT.
The emergence of therapies modulating the immune system posed new challenges, mainly in the form of the flare effect: an apparent progression of existing lesions and even the appearance of new lesions, when the patient is actually clinically improving. To adapt the existing guidelines to immunotherapies, a refinement of the Lugano classification was developed in 2016: LYRIC, the lymphoma response to immunomodulatory therapy criteria. These guidelines notably include the need for confirmatory imaging or biopsy, and introduced the indeterminate response (IR) in case signs of progression happen during the flare period (i.e. the first 12 weeks of treatment), to consider the flare effect.
The response criteria in lymphoma (RECIL) are other guidelines that were developed in 2017 to try and align lymphoma response criteria with the response evaluation criteria in solid tumors version 1.1 (RECIST 1.1). They aim to harmonize tumour assessment in trials where both lymphoma and solid tumours are treated. They include guidelines to determine response to treatment in case of FDG-avid lymphoma and FDG-non avid lymphoma, and they added the minor response (MR) category. There are few applications of these guidelines however, despite a 90% agreement rate at the end of treatment between Lugano and RECIL.
Thanks to its relative simplicity compared to the other criteria and its application to both HL and NHL, the Lugano classification is currently the gold standard for the assessment of lymphoma response to treatment in clinical trials.
However, the rapid development of new concepts, especially in the field of immunotherapy, might bring new evolutions.
For example, the promising lead of chimeric antigen receptor (CAR) T-cell therapies, assessed with FDG PET imaging, has different requirements in terms of PET acquisition timepoints compared to the current standard therapies. Besides, there is a need to identify CAR-T PET features to help in pre-treatment patient selection and in post-treatment response assessment.
The constant evolution of these technologies and their applications in clinical trials highlights the need for read criteria to be regularly rethought, updated and even replaced, in order to be as accurate as possible.
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