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 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.

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.

Data from the CAPItello trial showed a significant number of patients with PTEN deficiency experienced radiological progression without a corresponding PSA increase. This challenges the standard reliance on PSA for monitoring in high-risk prostate cancer and suggests a need for more frequent, personalized imaging protocols to detect progression earlier.

Experts believe molecular tests like Decipher and PTEN status are superior to simply counting bone lesions for guiding treatment. While not yet standard practice for all decisions, this represents a significant shift towards using underlying tumor biology to determine therapy, like adding docetaxel.

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.

A practical method to monitor radioligand therapy is a post-treatment SPECT scan. Since the therapeutic agent is radioactive, a simple planar scan about 24 hours after injection can visually confirm where the drug was delivered. This provides real-time feedback, beyond PSA levels, to potentially adapt treatment.

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.