A critical limitation of PSMA PET is its inability to detect tumors that do not express the PSMA protein. In these cases, a patient may show extensive disease on a conventional bone scan that is entirely invisible on a PSMA PET scan, highlighting the risk of relying on a single imaging modality.
A meta-analysis of over 9,500 patients in major prostate cancer trials, including the pivotal VISION and PSMA-4 trials for radioligand therapy, shows significant underrepresentation of Black and Hispanic patients. This creates a critical evidence gap when applying these therapies to diverse real-world populations.
NCCN now recommends PSMA PET as a potential replacement for traditional CT, MRI, and bone scans for initial staging of higher-risk prostate cancer and detecting recurrence. This shift is based on PSMA PET's superior sensitivity and specificity for finding micrometastatic disease, positioning it as a more effective frontline tool.
A significant real-world barrier to radioligand therapy is that the dose expires the day after its planned administration. This extremely tight window means that any patient travel issue, weather delay, or simple scheduling conflict can directly lead to a completely wasted, expensive dose, complicating treatment delivery.
Landmark clinical trials (CONDOR, SPOTlight) demonstrate that PSMA PET imaging effectively identifies recurrent prostate cancer in a high percentage of patients even with very low PSA levels. This challenges the traditional paradigm of waiting for higher PSA thresholds before imaging, enabling earlier and more precise intervention.
Even if most of a patient's cancer is PSMA-avid, the presence of small liver lesions that are *not* PSMA-avid is a major red flag. This can indicate a more aggressive, PSMA-negative biology that won't respond to PSMA-targeted therapy and may instead require alternative treatments like chemotherapy, complicating patient selection.