Abstract
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Objectives: Immune checkpoint inhibitors (ICIs) have recently emerged as one of the most important advances in cancer treatment. On the other hand, cancer patients treated with ICIs sometimes experience very poor prognosis called “hyperprogressive disease (HPD)”. HPD is usually defined as a RECIST progression at the first evaluation and as a ≥ 2-fold increase of the tumor growth kinetic ratio (TGKR) compared with pre-immunotherapy. Previous studies reported that HPD correlated with shorter progression-free survival (PFS) and overall survival (OS). At this moment, no useful method to predict the risk of HPD accurately before immunotherapy has been established, because its mechanism has not been elucidated. This retrospective study investigated 18F-FDG PET/CT findings of melanoma patients who demonstrated HPD after the start of ICIs. Then, we investigated the ability of baseline PET/CT parameters, acquired before the start of immunotherapy, to predict the risk of HPD. In addition, we evaluated whether we could diagnose HPD accurately based only on quantitative values obtained from baseline and first restaging PET/CT without information of TGR, a parameter that requires pre-baseline imaging before baseline imaging (3 time-point imaging).
Methods: Seventy-six patients (M, 49; F, 27) who underwent PET/CT scans before and approximately 3 months after immunotherapy from July 2010 to November 2018 were retrospectively enrolled. PET/CT parameters, including the sums of MTV, TLG, and the longest diameters of target lesions (total measured tumor burden, TMTB) based on irRECIST were measured from baseline PET/CT (MTVbase, TLGbase, and TMTBbase, respectively) and first restaging PET/CT (MTVpost, TLGpost, and TMTBpost, respectively). The ratio of MTV (MTVpost / MTVbase, MTVr), TLG (TLGpost / TLGbase, TLGr), and TMTB (TMTBpost / TMTBbase, TMTBr) before and approximately 3 months after immunotherapy were also calculated. These PET/CT parameters were compared between HPD and other patients. The area under the curves (AUCs) were used to assess the diagnostic performances of baseline PET/CT parameters to predict the risk of HPD, and those of MTVr, TLGr, and TMTBr to diagnose HPD without information of TGR. Kaplan-Meier survival analysis, and log-rank test were used for statistical analysis.
Results: Nine patients (M, 8; F, 1) met the criteria of HPD (11.8%) (TGKR ≥ 2, Fig. 1). MTVbase of the HPD patients was higher than that of non-HPD (TGKR < 2) patients (P = 0.037) and OS of HPD patients was worse than that of non-HPD patients (7 vs. more than 60 months, P = 0.0001) (Table). The AUC of MTVbase (> 155.45ml) to predict the risk of HPD was 0.703 (95% CI 0.585 to 0.804, P = 0.043), with a sensitivity of 66.7% and specificity of 81.2% (Fig. 2). The AUCs of MTVr (≥ 1.25), TLGr (≥ 1.15), and TMTBr (≥ 1.27) to diagnose HPD without information of TGKR were 0.875 (95% CI 0.775 to 0.941, P < 0.0001), 0.875 (95% CI 0.775 to 0.941, P < 0.0001), and 0.977 (95% CI 0.909 to 0.998, P < 0.0001), respectively, with all sensitivities of 100%, and specificities of 79%, 79%, and 83.9%, respectively (Fig. 3). One pseudoprogrssion case (1.3%) was seen in this population. MTVr, TLGr, and TMTBr of this case were 2.31 (> 1.25), 2.10 (> 1.15), and 1.62 (> 1.27), respectively, misdiagnosed as HPD when utilizing the ratio of tumor burden. TGKR of this pseudoprogression case was 1.29 (< 2.0).
Conclusions: Whole-body MTV of HPD patients at baseline PET was higher than other patients, but patients at high risk of developing HPD could not be accurately identified based on baseline PET/CT metabolic parameters prior to initiating immunotherapy. The ratio of PET/CT parameters before and approximately 3 months after the start of immunotherapy may be helpful to diagnose HPD, when patients do not undergo pre-baseline imaging, although distinguishing pseudoprogression from HPD must take into account the clinical assessment in addition to imaging.
Comparison of PET/CT findings between HPD and non-HPD patients
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