All that glitters is not gold: high uptake on PSMA PET in non-prostate cancers does not mean that treatment with [177Lu]Lu-PSMA-radioligand will be successful.

Background: The main objective is to discuss why treatment of non-prostate cancers with [¹⁷⁷Lu]Lu-PSMA-radioligand achieved only low tumor dose in most published cases, despite high uptake on PSMA PET. We use a patient with renal cell carcinoma as an illustrative example. Furthermore, we discuss how the problem with early washout and low tumor dose might be overcome by using a radionuclide with shorter half-life, matching the target binding residence time.

Case presentation: [⁶⁸Ga]Ga-PSMA-11 PET/CT of a 56-year old man with metastatic renal cell carcinoma showed high lesion uptake. One dose of 6.9 GBq [¹⁷⁷Lu]Lu-PSMA-I&T was administrated. Post-therapy dosimetry was performed with SPECT/CT and whole-body planar imaging after 5, 24 and 48 h. Doses to target lesions were only 0.2-0.5 Gy. No treatment effect was achieved.

Conclusion: Rapid tumor washout of [¹⁷⁷Lu]Lu-PSMA-I&T and low tumor dose despite high uptake of [⁶⁸Ga]Ga-PSMA-11 are most likely caused by localization of PSMA-receptors on neovasculature rather than on the tumor cells, and unlike in prostate cancer cells, the PSMA-RL / PSMA-receptor complex is not internalized. To overcome the problem with early washout, the use of a radionuclide with shorter half-life matching the target binding residence time will be needed.