Response Assessment in Lymphoma: The Lugano Classification and Beyond

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STANDARDIZING THE EVALUATION OF LYMPHOMA: HISTORICAL OVERVIEW

Although Cheson 2007 criteria made significant improvements over the original 1999 publication, there were assorted unresolved issues and challenges along with wide-ranging interpretations. This led to difficulties in comparing clinical trial outcomes. Some of the most challenging issues revolved around the manner of evaluating sites of disease involvement. Specifically, should measurable disease include both nodal and extra-nodal sites and, if so, how many total sites of disease should be followed? Since lymphomas can often involve solid organs, such as the spleen, leading to splenomegaly (and, at that time, a belief that it could also result in diffuse, non-focal liver enlargement), how should organ size be evaluated (e.g., visually, by volume, or by length) and what would constitute a threshold measurement for enlargement? There also remained uncertainty on how to evaluate bone marrow involvement (e.g., bone marrow biopsy vs. on ¹⁸F FDG PET uptake) and a requirement to consider clinical symptoms (e.g., B-Symptoms) in the outcome measurements. Finally, the evaluation of progression in Cheson 2007 was also widely interpreted in clinical trials. For example, progression could be met by an increase in the sum of perpendicular diameters (SPD) of all measured lesions, an increase in diameter of a single lesion, or by an increase in the product of the perpendicular diameters (PPD) of a single lesion. To address these ambiguities, the Cheson 2007 criteria was updated in 2014 following several consensus meetings in Lugano, Switzerland, and was cumulated into a final opinion paper for the 2014 updates.

The Lugano Classification

The Lugano Classification sought to remediate several past issues with the Cheson 2007 guidelines. The key features of Lugano that distinguish this criterion from the previously published guidelines included:

• Standardizing the staging of FDG-avid lymphomas
• Moving response by ¹⁸F FDG-PET for FDG-avid histologies away from a binary assessment of either presence/absence to a more robust 5-point visual scale based upon normal uptake in the liver and mediastinal blood pool activity as reference organs in which to rate ¹⁸F FDG uptake (Figure 1)
• Bone marrow biopsy were no longer indicated for the routine staging of HL and most DLBC. FDG-PET should be used instead for the assessment.
• Providing guidance on quantifying organ enlargement: spleen is considered enlarged on CT when vertical (cranial to caudal) length >13cm, and removing liver size as an organ of interest
• Providing clear guidelines that single lesion progression was consistent with Progressive Disease (PD) in which the Product of Perpendicular Diameter or PPD progression of single site clarified, and SPD progression no longer warranted
• Minimizing unnecessary scanning, thus avoiding undue radiation exposure

Implementing Lugano 2014 has been a step forward for the clinical trial community seeking to apply this criterion in new protocols or ongoing programs as it has placed the use of ¹⁸F FDG PET front and center in determining response. Despite the relative importance of ¹⁸F FDG PET over CT in determining response and progression for FDG-avid histologies, this may not necessarily apply to non-avid histologies or unknown FDG-avid lymphomas where CT assessments are essential for overall time point responses.