18F-FDG PET as biomarker in aggressive lymphoma; technical and clinical validation

Conclusion This thesis evaluated the role of [18F]FDG PET as a biomarker in aggressive lymphoma by both technical and clinical validation. It can be concluded that the role of [18F]FDG PET in treating aggressive lymphoma patients has clearly grown in the past years. Next to the role of [18F]FDG PET for the baseline staging and end-of-treatment response assessment in aggressive lymphoma, the value of interim [18F]FDG PET has become clearer. We validated that interim [18F] FDG PET has a high negative predictive value (>80%) when using Deauville and ΔSUVmax criteria for good response prediction in DLBCL. This has led to the inclusion of interim [18F]FDG PET guided treatment de-escalation in the current Dutch guidelines for DLBCL. Main findings/summary -For HL the interim [18F]FDG PET is important in clinical practice both for escalation of treatment as well as de-escalation of treatment. -Our systematic review showed that for DLBCL there is predictive value of interim [18F]FDG PET for 2-year progression-free survival (pooled hazard ratio of 3.13). Negative predictive values exceeded 80%, but positive predictive values (ranging from 20 to 74% between studies) were too low to allow for a risk stratified treatment approach in clinical practice (Chapter 3). -Interobserver agreement of Deauville scoring was 87.7% and 91.7% for interim and end-of-treatment [18F]FDG PET, respectively, asking for dual reads in clinical practice and central review in research (Chapter 4). -In the HOVON-84 study no added value of rituximab intensification of R-CHOP was found (Chapter 6b). Additional PET analyses showed that both interim [18F]FDG PET and age-adjusted international prognostic index are independent response biomarkers. Besides that, the external validation of semi-quantitative ΔSUVmax criterion outperformed the Deauville 5-point scale in the 2-year progression-free survival prediction (Chapter 6a) -In a phase II trial with MYC positive DLBCL patients the predictive value of interim [18F]FDG PET was limited (Chapter 7). -In the individual patient data meta-analyses from 1692 DLBCL patients from eight international studies, Deauville score and ΔSUVmax criteria were compared at different timing of the interim [18F]FDG PET after 2 and after 4 cycles (Chapter 8). ΔSUVmax criteria had a higher discriminative power and predictive value for 2-year progression-free survival than the Deauville 5-point scale (with a positivity cut-off for DS 4 and 5). The negative predictive values were high (above 80%) for all criteria, for both interim [18F]FDG PET after 2 and after 4 cycles. Positive predictive values were somewhat higher at interim [18F]FDG PET after 4 cycles compared to 2 cycles (ΔSUVmax 57% vs 46% and Deauville 4-5 43% vs 31%) and were higher for ΔSUVmax compared to the Deauville 4-5 positivity cut-off. In conclusion, good response (defined as ΔSUVmax ≥66%) after 2 cycles of R-CHOP treatment may qualify for randomized trials evaluating de-escalation of therapy regimens. Poor response (defined as ΔSUVmax <70%) after 4 cycles of R-CHOP treatment may qualify for evaluating new therapies in a randomized trial.