How appropriate use criteria for PSMA-PET imaging optimize patient care

In January 2022, the Journal of Nuclear Medicine (JNM) released appropriate use criteria (AUC) for prostate-specific membrane antigen (PSMA) PET imaging.1

In a recent interview, Hossein Jadvar, MD, PhD, MPH, MBA, FACNM, FSNMMI, discusses what the AUC consist of and why these criteria are vital in ensuring the individualized care of patients. Jadvar is a professor of radiology, urology, and biomedical engineering in the Keck School of Medicine and the Viterbi School of Engineering at the University of Southern California in Los Angeles, and former presidents of both the American College of Nuclear Medicine (ACNM), and the Society of Nuclear Medicine and Molecular Imaging (SNMMI).

Please discuss the background for the AUC regarding PSMA PET imaging.

Let me give you some background on where [the] AUC process came from. On March 31, 2014, the United States Congress passed the Protecting Access to Medicare Act of 2014. One of the parameters or components of this congressional act was that they tied advanced diagnostic imaging services, or ADIS, to physician reimbursement. That required the development and dissemination of these appropriate use criteria. The advanced diagnostic imaging services were considered to be magnetic resonance imaging, or MRI, computed tomography, or CT, and nuclear medicine, which includes PET. The idea was that after these AUCs are developed, they will be incorporated into what is called a clinical decision support mechanism. There are a number of them in the market. Then, the ordering professionals are supposed to consult these AUC documents and, according to typical clinical scenarios and scoring that are embedded into the AUCs, order specific imaging tests for their patients.

There are a number of entities that are able to develop these AUCs. [The] Society of Nuclear Medicine and Molecular Imaging, or SNMMI, is one of these national medical specialty societies that has been allowed to develop AUCs. Of note, the act prevented the insurance companies, or the patient advocacy groups to actually develop these documents. So, these are really limited to medical specialty organizations, or what they call 'provider-led entities’. The way it works is that there is a rather extensive process of how to develop these AUCs. It is primarily based on literature and evidence, systematic reviews, and analysis of those data. However, expert opinion can also enter into the picture to develop these AUCs for various types of clinical scenarios on a particular topic, and then the scenarios are scored by the expert panel. The expert panel is multi-specialty. The scoring is between 1 and 9. Scores 1 to 3 [are] considered to be 'rarely appropriate' for a particular clinical scenario. Scores 4 to 6 are considered to be 'maybe appropriate’; so, they're generally not appropriate but could be appropriate in a specific setting. Finally, the scores of 7 to 9 are considered 'appropriate' for a particular clinical scenario.

Please summarize some of the main points of the criteria.

This was an international multidisciplinary panel of 16 physicians who analyzed the data that have been published in literature through systematic reviews. In some cases, some expert panel information and ideas were also incorporated. PSMA is a very exciting development in the field of nuclear medicine, especially in the past several years with the recent approval of 2 tracers. One is Gallium 68 PSMA-11. That was approved back in December of 2020 for use at the University of California, San Francisco and the University of California, Los Angeles. And more recently, in May 2021, there was approval of the 18 F-DCFPyL, which is marketed as PYLARIFY by Lantheus for use in the clinic. So, we are very excited about that, and that also prompted the fact that there needs to be an AUC for these exciting new approved tracers. The AUC was developed, as I mentioned, through participation of multiple organizations, which are listed in the paper that was published. I refer you to see the list of the organizations. Sixteen physicians who represented these different organizations participated in this panel.

To summarize, there are 11 clinical scenarios, and each of these clinical scenarios were scored for the appropriateness of the PSMA PET imaging. Five of these scenarios are related to diagnosis and initial staging of prostate cancer. Three of them relate to the biochemical recurrence state of prostate cancer. And finally, 3 last scenarios relate to what we call the 'castration-resistant prostate cancer setting' of the disease.

The first scenario is related to the patients who have suspected prostate cancer, who are being evaluated for targeted biopsy and detection of intraprostatic tumor. We gave it a score of 3, which means it's rarely appropriate. There's limited evidence for this particular scenario, and we know that about 5% to 10% of prostate cancers may not express PSMA. However, there may be situations that PSMA may be considered in this case; for example, if the MRI is inconclusive, or there were prior biopsies that were negative. There are some clinical trials that are going to focus on this particular scenario, but at the moment, this particular clinical scenario was considered to be ‘rarely appropriate’ and given a score of 3.

The second scenario is patients with very low, low, or favorable intermediate-risk prostate cancer. These are patients who [have] already been diagnosed, and the question is with regard to initial staging of the disease. In this case, we gave it a score of 2, which [also] means ‘rarely appropriate.’ First of all, [we] took the risk stratification based on the [National Comprehensive Cancer Network] NCCN guidelines. In this particular scenario of very low, low, and favorable intermediate risk, usually imaging is not indicated in many cases. Therefore, initial management can be sometimes observation or active surveillance. Therefore, because of the paucity of evidence and recommendations from the NCCN guidelines, we decided that this is ‘rarely appropriate’ with a score of 2.

Scenario 3 is the patients who were newly diagnosed with unfavorable intermediate, high, or very high-risk prostate cancer. As opposed to scenario number 2, there is rather ample evidence in this particular scenario, and therefore the score was given 8 as ‘appropriate.’ There have been a number of trials that have been published, including proPSMA from Australia, and OSPREY [NCT02981368], which is based on the PyL. The data and evidence were quite strong in this setting, and that's why we gave it a score of 8 for this scenario.

Then, we go to scenario number 4. This is newly diagnosed, unfavorable intermediate, high, or very high-risk prostate cancer with negative or equivocal conventional imaging, or if there is oligometastatic disease seen on conventional imaging. Now, conventional imaging is considered to be [a] bone scan [or] contrast-enhanced CT of [the] abdomen and pelvis, [and] in some cases, chest CT. Oligometastatic disease is typically defined as 1 to 3 metastatic lesions seen on imaging. So, these [cases] are very low-burden metastatic disease. In this clinical scenario, we gave it a score of 8, or ‘as appropriate.’ Again, this is based on NCCN guidelines risk stratification, and it was recognized that conventional imaging often underestimates the extent of metastatic disease. There have been studies that have shown that PSMA PET can [be] significantly useful in this scenario, showing additional burden of disease which was not apparent on conventional imaging.

Then, we move on to scenario number 5, which is newly diagnosed prostate cancer with widespread metastatic disease on conventional imaging. In this case, the panel decided to give it a score of 4, which is interpreted as 'maybe appropriate.' The idea here is that there is little evidence that if you know there are more lesions than what is seen on conventional imaging or multiple lesions—what we call polymetastatic disease—there is really little additional value that PSMA PET may provide in this specific case, because the management does not typically change much. However, we are awaiting the approval of PSMA radioligand therapy based on the very favorable results of a recent clinical trial called [the] VISION trial [NCT03511664] that were published recently in the New England Journal of Medicine.2 So, based on that and the fact that the PSMA PET may be useful to show the evidence of metastatic disease and PSMA expression before radioligand therapy, the panel decided that the best score at this point is 'maybe appropriate' or a score of 4.

Then we move on to scenario number 6. This is under biochemical recurrence of the disease. This scenario relates to PSA persistence, or PSA rise from [an] undetectable level after radical prostatectomy. The panel gave it a score of 9, which is the highest score you can give. This is really what's considered to be appropriate. There is a really good, high-level of evidence at this point that has been published both for gallium 68 PSMA-11 and for PYLARIFY, based on a number of trials like CONDOR [NCT03739684] and OSPREY for the PyL tracer and other trials that have been published. So, we gave it a score of 9 in this case.

Then, we move onto scenario 7. This was PSA rise, or biochemical recurrence, after definitive radiotherapy for their prostate cancer. This was also given a score of 9 or 'appropriate' with a similar reasoning as I gave for the previous scenario with radical prostatectomy.

Then, we go to scenario 8. This is PSA rise after focal therapy of [a] primary tumor. The panel decided to give it a score of 5, which is 'may be appropriate.' This is because there are limited data in this particular scenario, and it is unclear what biochemical recurrence means in the setting of focal therapy, which is usually reserved for low or very low-grade primary tumors.

Then there's scenario 9. Now, we are getting under the castration-resistant prostate cancer category. In this case, scenario 9 was non-metastatic or M0 CRPC castrate-resistant prostate cancer on conventional imaging. In this case, the panel decided to give it a score of 7, or 'appropriate.' It was recognized that in many cases with conventional imaging, what we call 'non-metastatic' actually turns out to be metastatic when you do it with a more accurate, more sensitive test, such as the PSMA PET. That can have ramifications. If the patient on PSMA PET is shown to have oligometastatic disease, then there are some data out there that show that metastatic-directed therapy may be beneficial in these patients. Or if it turns out that the patient, in fact, has polymetastatic disease, of course that also has management ramifications with regard to systemic therapy. In that setting, and because of the higher sensitivity of PSMA PET, it was decided that a score of 7 should be given as appropriate for this scenario.

Then we get into scenario 10, which is a post-treatment PSA rise in metastatic castrate-resistant prostate cancer. This was given a score of 6, which is 'may be appropriate.' Again, in this case, as was discussed before in a different scenario, it was not exactly clear at this time what would be the management impact of knowing that there are more metastatic lesions than what you already see on conventional imaging. However, because of the horizon for the approval of the PSMA radioligand therapy based on the VISION trial that I mentioned, the panel decided that a score of 6 would be appropriate at this time. I should mention that these appropriate use criteria will be revisited every year and any new information or relevant literature that is published will be evaluated and the scores may change, or new scenarios added. So, for example, in this scenario, which is currently a score of 6, this score may be revised to a higher score when PSMA RLT, or radioligand therapy, becomes available and approved.

Scenario 11 was evaluation of response to therapy. This was given a score of 5, or 'may be appropriate' because there are relatively limited data in this case and we still [don't] understand exactly how different drugs, whether there are currently approved drugs or emerging drugs, affect the PSMA expression in the tumor. It is also known that androgen axis-type drugs may affect the PSMA expression in different ways depending upon the state of the tumor or the duration of the treatment. So, because of these issues and the need for more experience, literature, [and] evidence on this specific scenario, it was decided that it should be given a score of 5, [or] 'may be appropriate.'

What changes in the management of prostate cancer do you foresee in the future after these criteria are adopted?

The hope, of course, and I think it is a requirement at this point, [is] that clinicians consult the AUC document and therefore choose the appropriate imaging modality for their patients. So, this is an attempt to provide the clinicians with the most recent available data and evidence, and therefore tell them how imaging, in this case PSMA PET imaging, may affect their decision-making for the treatment and management of their patients.

What is the take-home message for the practicing urologist and for the patient?

I hope that our clinician colleagues in urology, medical oncology, and radiation oncology, as well as patients, consult and see this particular document, [It] was recently published and is available [for] free on the JNM website or the SNMMI website.They can see how PSMA PET can help the clinical management of the patient in specific clinical situations. I think [in] this way they can optimize the care of the patient.

Is there anything else you feel our audience should know about this particular topic?

I think PSMA PET, as I mentioned, has been an exciting development in nuclear medicine and in prostate cancer management. This is a rapidly moving kind of development, and I think there will be more data that will become available. We are very hopeful that, as I mentioned, the PSMA radioligand therapy becomes FDA approved soon so that the patients can benefit from this innovative treatment, which is also based on PSMA. I hope that both the clinicians and the patients, just like us, keep up with the developing data that comes [out] with this particular tracer.

References

1. Jadvar H, Calais J, Fanti S, et al. Appropriate use criteria for prostate-specific membrane antigen PET imaging. J Nucl Med. 2022;63(1):59-68. doi:10.2967/jnumed.121.263262

2. Sartor O, de Bono J, Chi KN, et al. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322