Standard guidelines for treating metastatic prostate cancer are based on conventional imaging (CT/bone scan). The panel argues that PSMA PET-positive biochemical recurrence represents a different, earlier disease state. This necessitates new treatment paradigms, like definitive therapy durations, not covered by current guidelines.

The effectiveness of radioligand therapy is counterintuitive: as tumors shrink and PSMA binding sites decrease, less radiation is delivered to the cancer. The VISION trial showed the first two doses delivered more radiation to the tumor than the subsequent four, questioning the value of a fixed, prolonged treatment schedule.

The advent of highly sensitive PSMA PET imaging identifies metastases in many patients previously considered to have only biochemical relapse (BCR). However, experts argue against a knee-jerk reaction to treat. Many of these patients, particularly those with slow PSA doubling times, can be safely observed, challenging the assumption that visible disease always requires immediate intervention.

Unlike traditional chemotherapy, radioligand therapy's toxicity may be inversely correlated with tumor volume. In low-burden disease, fewer cancer cells act as a 'sink' for the drug, potentially leading to higher radiation exposure and side effects in healthy, PSMA-expressing tissues like salivary glands.

In cases of suspected glioma recurrence post-radiation, FET PET imaging can provide a more accurate diagnosis than MRI perfusion, even when MRI findings suggest tumor growth. This allows clinicians to avoid unnecessary changes in therapy based on potentially misleading MRI data.

An NCI working group coined "PSMA positive BCR" to classify patients with biochemical relapse (BCR) who have findings on a modern PSMA PET scan. This formally recognizes this group is distinct from both conventionally-defined metastatic patients and traditional BCR patients, necessitating unique clinical trial designs and treatment strategies.

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.

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.