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After radical prostatectomy, waiting for the prostate-specific antigen (PSA) level to rise high enough to obtain insurance-approved prostate-specific membrane antigen (PSMA)-PET imaging may increase mortality risk for men with at least one high-risk factor, new research suggests.

Because there is a lower chance of correctly identifying recurrent disease at PSA levels <0.2 ng/mL, many insurers in the United States do not reimburse for a PSMA-PET scan unless the patient has documented PSA failure (i.e., ≥0.20 ng/mL and rising). As a result some physicians choose not to obtain a scan and start salvage radiation therapy until the PSA level well exceeds 0.20 ng/mL to levels of 0.30 ng/ml or higher, explained Anthony D'Amico, MD, PhD, of Brigham and Women's Hospital and Dana Farber Cancer Institute in Boston, and colleagues.

As detailed in the study in the , to assess whether this was safe, the team analyzed data on more than 25,000 patients with at least one high-risk factor (pGleason 8-10 or pT3 or pT4) treated with radical prostatectomy from 1990 through 2020. The researchers used multivariable Cox regression analysis to examine all-cause mortality risk when salvage radiation therapy was delivered at PSA levels ranging from 0.10 to 0.50 ng/mL, in 0.05 ng/mL increments. They adjusted for age, year of radical prostatectomy, established prostate cancer prognostic factors, institution, and the time-dependent use of androgen-deprivation therapy.

The study found that patients who received salvage radiation therapy at PSA levels higher than 0.25 ng/mL had a 49% increase in all-cause mortality risk (95% CI 1.11-2.00, P=0.008). The result was similar when prostate cancer-specific mortality risk was examined (HR 1.43, 95% CI 0.80-2.55), with the results showing no significant increased risk in all-cause mortality at PSA values below 0.25 ng/mL.

"The results of the current study provide evidence to support that waiting to initiate salvage radiation therapy after PSA failure may place some patients at increased all-cause mortality-risk," D'Amico and colleagues concluded.

In the following interview, D'Amico, who is chief of Genitourinary Radiation Oncology, discussed additional details and considerations:

How should the results of this study impact clinical practice?

D'Amico: Physicians should obtain PSMA-PET imaging no later than a PSA level of 0.25, and then initiate salvage radiation therapy -- and as appropriate, androgen-deprivation therapy -- to avoid a potential for increased risk of death from prostate cancer.

Your study adjusted for the time-dependent use and duration of androgen-deprivation therapy. Why was that important?

D'Amico: The reason for the adjustment for the time-dependent use of androgen-deprivation therapy is that it is known in the post-prostatectomy setting that immediate use of adjuvant androgen-deprivation therapy in men with high-risk factors such as pelvic node positivity improves survival and therefore could serve as a confounding factor that could impact the robustness of the results if not adjusted for.

A prospective randomized trial is currently investigating whether PSMA-PET guided therapy improves outcomes. Can you tell us about that?

D'Amico: There is an ongoing that enrolls people at a PSA level of 0.1 or higher -- so a level low enough that it probably will be very relevant to the current study findings of starting before 0.25 -- and what it does is it randomizes men to either PSMA-PET or conventional imaging and then bases the recommended treatment on the results of those imaging studies. The primary endpoint is PSA recurrence-free survival based on PSA, which will answer whether using PSMA-PET as opposed to conventional imaging following PSA rise after radical prostatectomy can reduce the risk of recurrence as measured by a PSA rise.

How do your study results relate to the findings of the clinical trial?

D'Amico: RADICALS-RT was a study in which men were randomized to adjuvant radiation or early salvage at a PSA of 0.1. The RADICALS-RT team showed that in these patients who had at most one high-risk factor -- there were very few with two high-risk factors -- there was no difference in the long-term outcome of progression-free survival.

This supports exactly what we have here, and that is if you start salvage RT [radiation therapy] at a PSA level of 0.1 you do not increase the risk of recurrence in men with at most one high-risk factor. There are that suggest in men with two high-risk factors, RT should be delivered prior to the PSA reaching 0.10 ng/L to not increase all-cause mortality risk.

Finally, is there anything else you would like to make sure oncologists understand about your study or this issue?

D'Amico: If a physician orders a PSMA-PET and it gets denied, they should use this study to deal with the insurance company, because this study provides evidence to support that if they wait longer there is a potential impact on survival. PSMA-PET is often denied until a PSA of 0.3 or even as high as 0.5.

That's one reason why we performed this study, to help alleviate the insurance issue that's going on in the United States. It's not going on in Australia, where people can get a PSMA-PET at a PSA level of 0.10 or higher.

Read the study here.