It's a complementary technique. PET has a high sensitivity, informs on biological signal. SPECT is linked to therapy, provides dosimetric information, and provides information on the therapy delivery, both inform on biology. So when we look at cases, this is a classic case of progression of mCRPC metastatic to bone during treatment. This is the PSMA PET after the second cycle, which, concordantly with a PSA elevation demonstrates increased disease. You see the dural-based lesion. And this is a classic case of concordant PSA and imaging response in mCRPC metastatic to bone at the second cycle, but things are not always like this and clear-cut. So what is it that we are measuring? So the most obvious and immediate parameter is the uptake, basically with SUV max, but also SUV mean. We measure whole-body metrics, which are becoming more and more important. So the tumor volume, the total lesion PSMA volume, and also we obtain with that the absorbed dose. So those parameters correlate with overall survival, progression-free survival, and PSA response. So let's examine the course of the treatment. So we have baseline predictive parameters thresholds. Let's start with PSMA PET SUV mean.
As demonstrated in the TheraP trial, SUV mean at least of 10, it's the gold standard cutoff. It correlates with a PSA-50 response in both arms. So a higher SUV mean correlates with a greater response of the PSA, both, in both arms of the trial. The post-hoc analysis of the vision trial demonstrated that patients in the highest quartile of uptake had a better radiographic progression-free survival and overall survival compared to the lower quartile. And also in the US expanded access program, the baseline total volume SUV mean correlated with a PSA-50 response, and was in the multivariate analysis an independent predictor of the PSA related progression-free survival and overall survival. PET volume is also very important, as was demonstrated in the TheraP trial, the FDG PET, not PSMA PET volume greater than 200 ml was correlated with a PSA response and radiographic progression-free survival and was the only independent predictor across all treatments of a lower survival. And if we consider the PSMA PET volume metrics, both the total lesion PSMA and the total lesion quotient, which is the total volume divided by the SUV mean, which correlates also with a worse prognosis, meaning that higher tumor burden and a low PSMA expression indicates worse outcome.
So now... Sorry. The key message of the PSMA PET versus SPECT. So this is a trial that evaluated 102 patients with a PSMA SPECT acquired at the second cycle. When the SPECT results were combined with the PSA level, there was an agreement with a volume, with a response based on the PET RECIP criteria. So the PET obtained at baseline. So both techniques, so the volume response on SPECT, correlated with the overall survival prediction, the PET was superior for PSA prediction. So the response noted on SPECT at the second cycle never corresponded to POD to the progression at the second cycle PET, and the progression on SPECT was always confirmed by PET. So we can conclude that lutetium PSMA SPECT offers a practical, cost-effective alternative, with comparable overall survival prognostication. So in treatment, we can obtain a PSMA PET. We can categorize the response with a PPP criteria.
We can categorize the response with the RECIP criteria, which divide categories of response based upon their correlation with the overall survival. And on treatment response thresholds tell us that thresholds of plus/minus 30% in volume give us an optimal discrimination between partial response, stable disease, and progressive disease, and they are significantly separated based upon the different overall survival associated with them. And these changes were demonstrated to be superior to PSA change or new metastasis alone. There is also a recent demonstration that a visual score, or if you want, an eyeballing evaluation of the PET scan, in treatment PET scan, can provide an association with a median PSA related progression-free survival. What about the SPECT? The cycle-2 SPECT, evaluation with the Cycle-2 SPECT demonstrates that any increase in the SPECT volume predicts shorter PSA-related progression-free survival, in various trials.
The RECIP criteria applied to SPECT, like a 20% total volume increase with the appearance of new lesions, correlated with the reduced PSA PFS, reduced overall survival, and obviously new bone lesions were a strong overall survival predictor. And the cycle-1 SPECT SUV mean was an independent predictor of PSA-50 response and PSA PFS. So the relevance of increasing SPECT CT volume, this comes from the LuPIN trial, which is the association of lutetium PSMA and a radiosensitizer. So the increasing volume on serial lutetium PSMA SPECT predicts a shorter PFS, PSA, PFS, and notably the identified progression also in patients who didn't have a clear increase in PSA levels. This is one case of our series. A patient clearly demonstrated increasing lung metastasis despite a mild increase of PSA levels. We can also look at biomarkers from the point of view of the dose dosimetry, so the dose-response relationship, the dosimetric dose of the lesion in terms of dose-response relationship. This is our 65 patient series that we studied with single and multiple time point voxel dosimetry.
First things first, on the left, we noted a strong correlation between the baseline PET and the SPECT SUV MAX. And on the right, you can see that the mean absorbed dose correlated with the response. So the mean absorbed dose greater than 7.5 grays at the first cycle correlated with a better PSA response and a longer PSA PFS. So when to use SPECT versus PET, acceptable SPECT in high-volume disease, it's acceptable during lutetium PSMA therapy. PSMA PET is preferred in a small disease, like small nodes, like the case you can see depicted there, and for eligibility determination for treatment. Let's not forget that the PSMA PET informs on the first side of the equation of the response, which is the dose to the tumor. We also have to account for the radioresistance, and from our experience with the radiosensitivity marker PPQ in neuroendocrine tumors to inform at baseline who would respond to lutetium dotatate therapy, we can go to prostate cancer theranostics, and emerging data in this field suggests that genomic biomarkers can inform on lineage plasticity and genomic programs that modulate PSMA expression and radiosensitivity. So in conclusion, the take-home points. Baseline patient selection is critical.
The uptake is the most robust validated predictor for value... Sorry, for lutetium PSMA candidacy. The high volume is, identify poor prognosis regardless of treatment, whole body PET metrics outperform lesion-based or PSA only assessment. The two PET and SPECT techniques are complementary, not competing. Dosimetry refined imaging-based response and emerging genomic biomarkers are and are clarifying and will clarify heterogeneity and resistance. With this, I would like to thank the group that I work with and thank you very much for your attention.