Undetectable psa after radiation and hormone therapy

Raoul S. Concepcion, MD, FACS: Brian, how do you define PSA [prostate-specific antigen] nadirs, because I think this is an important point, in the surgical patient and in the radiotherapy patient?

Brian Helfand, MD, PhD: Ultimately after surgery, when we take out the entire prostate, we’re really expecting that PSA to go to a value of undetectable, 0 [ng/mL]. There are certain definitions, because we use ultrasensitive assays, etc. For the most part, we want to see that at what an equivalent value is of 0 [ng/mL]. At our institution, that is less than 0.02, or less than 0.001 [ng/mL], which I have seen depending on the assay. If after surgery that level rises to a value of 0.2 [ng/mL], I think everyone would agree this is a common definition that would be considered a recurrence. There has been some evolution, especially for men with higher-risk disease, that if you’re using an ultrasensitive assay and you are seeing consecutive rises of that PSA before they’re actually getting to a value of 0.2 [ng/mL], most people would agree that that’s a recurrence as well. There is some devil in the details there, but certainly, I think if you’re going to walk away with this, the value of 0.2 [ng/mL] after a surgery would be considered a recurrence.

For radiation, it becomes a little trickier because we still have the prostate gland that’s in situ, and there is some benign tissue there, so there is for many patients, a level of PSA that exists. Your PSA will get down to some lowest value, or that nadir value. There have been various definitions that have been used throughout the years. I typically use what’s referred to as the Phoenix definition, which is a value of 2 ng/mL greater than their lowest value. Again, if you see consecutive rises at least a month apart, consistently rising more than would be expected, I also have some suspicion there that earlier intervention or recurrence may be warranted.

Raoul S. Concepcion, MD, FACS: Judd, we know that in the surgical patient, that nadir happens quickly, usually within 6 months, if it’s going to get to the level that Brian was discussing. What about with the radiation? When do you start to say, “OK, I’m at 6 months, I’m at 12 months, or I’m at 18 months?” When do you feel comfortable? I think as Brian pointed out, it’s not going to go to less than .001 or less than .02 [ng/mL]. What does that time frame look like in the radiation patient?

Judd W. Moul, MD: That’s a great question. In the classic teaching, in the era before androgen deprivation therapy [ADT] was used with radiation, the radiation therapy itself would sometimes take up to 18 months to clear the prostate cancer. Therefore, we’ve been always taught that you need to sometimes wait up to 18 months if it’s a patient who’s just receiving radiation, and you wouldn’t necessarily want to do a biopsy. You also have a PSA bounce phenomenon that sometimes can occur. Now, all the high-risk patients and many of the intermediate-risk patients are also receiving ADT with the radiotherapy. With the ADT, their PSA should go down generally more quickly, especially if you’re using an antagonist like Degarelix, or now the new oral option, relugolix. In general, the PSA typically nadirs, I see it nadir usually within 3 to 6 months in men who are getting hormone therapy with radiation.

The only additional point that I would make is that sometimes in guys who had low-risk or intermediate-risk disease and had a modern-era radical prostatectomy [RP] with aggressive nerve sparing, bladder neck sparing, and urethra sparing, we see low levels of PSA that are not cancer-related. Therefore, I agree with Brian that in the high-risk patients, you can jump on a PSA recurrence quickly, but I would caution the oncologists in our audience tonight that you must look at the RP pathology. Moreover, if it was not so bad pathology, and if the guy has a PSA of 0.13, or even 0.2 [ng/mL] a couple of years out, I tend to follow those patients because there is this phenomenon of benign glands at the margin. We know from the Mayo Clinic’s series and our work at Duke [Cancer Center], that honestly, sometimes up to 30% of patients can have this in long-term follow-up, a little bit of PSA in the system that’s not cancer-related.

Transcript edited for clarity.

Media contact: Nicole Fawcett, 734-764-2220 |  Patients may contact Cancer AnswerLine 800-865-1125

Analysis finds PSA levels predict which men with recurrent prostate cancer will be harmed by adding long-term hormone therapy to radiation

Undetectable psa after radiation and hormone therapy

Daniel Spratt looks at a prostate scan with a colleague

CHICAGO — A secondary analysis of a recent clinical trial that changed the standard of care for men with recurring prostate cancer finds long-term hormone therapy does more harm than good for many men and calls for rethinking treatment guidelines based on a patient’s post-operative prostate-specific antigen (PSA) level. Findings were presented at the 61st Annual Meeting of the American Society for Radiation Oncology (ASTRO) in Chicago.

The study reanalyzed data from NRG Oncology/RTOG 9601, a randomized, phase III clinical trial initially reported in 2017 that found adding two years of anti-androgen therapy to post-surgical radiation treatment for men with recurring prostate cancer increased their long-term overall survival rate. That study led to the recommendation that men with recurrent prostate cancer be treated with both radiation and long-term hormone therapy after surgery.

However, a secondary analysis of this data, splitting patients into those with high and low PSA levels, has found that men with low PSAs after prostate surgery gained no overall survival benefit from long-term hormone therapy and greatly increased their risk of dying from other causes.

“What we showed for the first time is that a patient’s PSA level is a predictive biomarker,” says Daniel Spratt, M.D., formerly the Laurie Snow Research Professor of Radiation Oncology and chair of the Genitourinary Clinical Research Program at the University of Michigan Rogel Cancer Center. “That is, you can use a patient’s PSA to better select which men should receive hormone therapy, and to predict who will benefit and who will not benefit from this treatment, and who may actually be harmed by it.

“We found that the lower the PSA, the more harm the patient experienced. The higher the PSA, the more likely the patient was to benefit from hormone therapy because it decreased their chances of dying from prostate cancer and resulted in improved overall survival rates,” says Spratt, who presented the data.

Spratt and colleagues Robert Dess, M.D., Matthew Schipper, Ph.D., and Yilun Sun, Ph.D., re-examined data for 760 patients treated between 1998 and 2003 at more than 100 centers across North America whose cancer returned following surgical removal of the prostate. In the original study, patients were randomized to either post-surgical radiation therapy plus a nonsteroidal anti-androgen or placebo for two years, and overall survival rates were compared.

In this secondary analysis, researchers first divided patients into two groups based upon their PSA levels prior to radiation: those with PSAs greater than 1.5 ng/mL (n=118) and those with PSAs lower than 1.5 ng/mL (n=642), which was a stratification factor on the trial. As in the original study, they found a significant improvement in overall survival rates for patients whose PSA was higher than 1.5 ng/mL. However, there was no overall survival benefit for men with PSA levels lower than 1.5 ng/mL.

Spratt says he wanted to re-examine what happened to patients with lower PSA levels in light of changes over the past two decades in how recurrent prostate cancer is treated. At the time the RTOG 9601 trial was enrolling patients, he says, it was standard to allow PSA to rise to high levels following radical prostatectomies before initiating radiation therapy, but that’s no longer the case.

“The current standard is that, after surgery, if the PSA becomes detectable at very low levels – the lower the better – we recommend giving radiation,” he says.

The researchers therefore further analyzed data for a subset of patients with PSA levels less than or equal to 0.6 ng/mL (n=389), closer to today’s standard for post-surgical radiation treatment. They found that this group was twice as likely to die from causes other than cancer when hormone therapy was added, with the greatest risk of death for those with the lowest PSA levels. This subset of patients was also between three and four times more likely to experience a combination of severe cardiac events and neurological.

“We went into this study expecting that men with low PSAs probably would derive minimal benefit from hormone therapy, but we were surprised at the magnitude of harm that these patients experienced,” Spratt says. “A lot of these side effects have been reported over the past few decades but demonstrating this in a clinical trial to this extent has not been done before.”

Based on these findings, Spratt says he believes clinical guidelines for treating men with recurrent prostate cancer should be reconsidered.

“For post-operative patients with low PSAs, they do very well with just radiation therapy after surgery. They actually have very good long-term outcomes,” he says. "Patients with high PSAs, over 1.5 ng/mL, should continue to receive long-term hormone therapy in addition to radiation. It improves their survival substantially.

“But for patients with PSAs below 0.6 ng/mL who receive post-operative radiation therapy, there needs to be a real discussion about the fact that hormone therapy has not been shown to help these men live longer,” he adds. “Our study shows that long-term hormone therapy could actually hurt their survival and cause them other problems. A lot of shared decision-making is needed before recommending hormone therapy to all men with low PSAs.”

Spratt and his colleagues are currently enrolling post-operative patients with prostate cancer in another study that will delve deeper into who might benefit from hormone therapy and who might not, based on genetic testing of their tumors (BALANCE trial/NRG GU-006).

Citation: “Two years of anti-androgen treatment increases other-cause mortality in men receiving early salvage radiotherapy: A secondary analysis of the NRG Oncology/RTOG 9601 randomized phase III trial,” presented Monday, Sept. 16, at ASTRO’s 61st Annual Meeting in Chicago

Press release courtesy of ASTRO

What should PSA be after radiation and Lupron?

Recent studies have shown that for optimal results, PSA levels should be lower than 1 ng/ml, and even lower than 0.5 ng/ml. Levels that are above 1 or 2 ng/ml 12 to 18 months following completion of radiation treatments are very worrisome, because they indicate that the cancer may not have been eradicated.

What is an undetectable PSA after radiation?

For example, after radical prostatectomy, PSA is expected to drop to a level of 0.1 ng/mL or below, which is defined as undetectable, and remain there for the rest of the patient's life.

Can PSA stay low after hormone treatment?

Some men find that their PSA level falls for a few months, or sometimes longer. The side effects of anti-androgens can be similar to the side effects of other types of hormone therapy and can include breast swelling and breast tenderness. Read more about the side effects of hormone therapy.

Does undetectable PSA mean remission?

Ideally, your post-prostatectomy PSA will be undetectable, or less than 0.05 or 0.1 nanograms of PSA per milliliter of blood (ng/mL). If that's the case, your doctor may call it a remission.