Tumor sink effect in 68Ga-PSMA-11 PET: Myth or Reality?

Background: We aimed to systematically determine the impact of tumor burden on the 68Ga-prostate-specific membrane antigen-11 (68Ga-PSMA) PET biodistribution by the use of quantitative measurements. Methods: This international multicenter retrospective analysis included 406 men with prostate cancer who received 68Ga-PSMA PET/CT. Of these, 356 had positive findings and were stratified by quintiles into very low (Q1, ≤25 ml), low (Q2, 25-189 ml), moderate (Q3, 189-532 ml), high (Q4, 532-1355 ml) and very high (Q5, ≥1355 ml) total PSMA-positive tumor volume (PSMA-VOL). PSMA-VOL was obtained by semi-automatic segmentation of total tumor lesions using qPSMA software. Fifty prostate cancer patients with no PSMA-positive lesions (negative scan) served as control group. Normal organs, which included salivary glands, liver, spleen and kidneys, were semi-automatically segmented using 68Ga-PSMA PET images and average SUV (SUVmean) was obtained. Correlations of PSMA-VOL as continuous and as categorical variable by quintiles with SUVmean of normal organ were evaluated. Results: The median PSMA-VOL was 302 ml (interquartile range [IQR], 47-1076). The median (IQR) SUVmean of salivary glands, kidneys, liver and spleen was 10.0 (7.7-11.8), 26.0 (20.0-33.4), 3.7 (3.0-4.7) and 5.3 (4.0-7.2), respectively. PSMA-VOL showed a moderate negative correlation with SUVmean of salivary glands (r=-0.44, p<0.001), kidneys (r=-0.34, p<0.001), and liver (r=-0.30, p<0.001) and a weak negative correlation with spleen SUVmean (r=-0.16, P = 0.002). Patients with very high PSMA-VOL (Q5, ≥1355 ml) had a significant lower PSMA uptake of salivary glands, kidneys, liver and spleen compared to the control group with an average difference of -38.1%, -40.0%, -43.2% and -34.9%, respectively (p<0.001). Conclusion: Tumor sequestration affects 68Ga-PSMA biodistribution in normal organs. Patients with very high tumor load showed a significant lower uptake of 68Ga-PSMA in normal organs confirming a tumor sink effect. As similar effects might occur with PSMA-targeted radioligand therapy, these patients might benefit from increased therapeutic activity without exceeding the radiation dose limit for organs at risk.