Originally published 8/15/2019
In 2000, Rudy Giuliani (then Mayor of New York City) became the poster boy for brachytherapy (BT). This treatment, involving the permanent implantation of radioactive seeds in the prostate gland, was still fairly new for treating localized prostate cancer (PCa).
Perhaps because Giuliani was a public figure, the number of patients choosing BT quickly surged, peaking in 2002 at 16.7% of patients, according to a 2019 medical bulletin; after that, however, BT use “steadily declined to a low of 8 percent in 2010….By 2016, only 5.1 percent were treated with BT…”
This trend can be partly explained by the growing use of Active Surveillance for low-risk PCa, the development of more accurately targeted beam radiation methods, and the advent of precision focal therapy modalities.
Now, an Oct. 2024 Australian study in the journal Brachytherapy adds another possible explanation for the drop in BT use as a primary treatment: its long-term cancer control may not be as effective as other treatments. The paper by Loos, et al. reports on 40 brachytherapy patients who were followed for an average of 7 years, and who underwent PSMA PET/CT scans triggered by rising PSA (suspected biochemical recurrence). The authors found that 50% had recurrence in the prostate gland. Of those, 40% had recurrence in a high-dose radiation zone.[i] In all cases, the PSA rise that triggered imaging occurred well past the period in which a PSA bounce is common (see blog below), so it’s good that they were scanned so appropriate salvage treatment could begin. That said, the recurrence rate cited in this study does not support BT as an effective treatment.
Prostate specific antigen (PSA) is like an ID tag for prostate cells. Each prostate cell, whether normal or cancerous, carries proteins (antigens) that can be “shed” into the bloodstream when some type of activity stimulates the prostate. Generally, the more constant the activity, the higher the level of PSA as measured by a simple blood test.
What kind of activity releases these proteins? Temporary activity like sexual stimulation, riding a bike, or a digital rectal exam causes a short-term spike in PSA. Ongoing activity like a prostate infection, inflammation, BPH (a noncancerous aging-related gland enlargement), or a prostate cancer tumor can cause a longer-term elevation and/or rising PSA. It’s good to periodically check PSA blood levels PSA communicates about prostate activity. Yet there’s no way to know WHAT the activity is without further exploration in the form of imaging, biopsy, etc.
PSA after non-radiation prostate cancer treatment
If a rise in PSA leads to testing that reveals a diagnosis of localized prostate cancer (PCa), the patient may seek treatment. Each type of treatment has an effect on PSA:
- Radical prostatectomy (surgical removal of the prostate) makes PSA undetectable in 6 weeks, because all prostate cells including PCa cells have been taken out of the body. If PSA remains undetectable for the rest of a patient’s life, it means surgery was a success.
- Ablating the whole gland (destroying it within the body) is done as a minimal-to-noninvasive “equivalent” of prostatectomy, using methods like freezing (cryo) or HIFU. This leaves harmless prostatic scar tissue inside the body. PSA drops to near-undetectable levels in 6 weeks (the scar tissue still has surface antigens) and is expected to stay there for the rest of the patient’s life.
- Focal PCa ablation will lower the PSA in 6 weeks because the tumor is destroyed. However, with healthy prostate tissue left in place it is expected that future blood tests will reflect the presence of low PSA levels due the activity of the normal cells.
PSA drop is different after radiation for prostate cancer
Radiation, whether beam radiation or brachytherapy (seed implants), causes a lowering of PSA about 12-14 months later. This is because radiation gradually exerts damaging “pressure” on PCa DNA so cells begin to die off. Also, they are unable to reproduce themselves. (Healthy prostate cells and nearby neighboring structures are more resistant to the effects of radiation, but it’s not uncommon for radiation to irritate the bladder, bowel, and nerves that control sexual function—at least temporarily.)
Doctors regularly monitor PSA after radiation. They need to know when it reaches its nadir (lowest point). It could go as low as zero (undetectable) but more often the value will range from a fraction above zero to 2 ng/ml.
Once the PSA reaches nadir, it should remain stable for the rest of the patient’s life. However, about a third of post-radiation patients have what is called a PSA bounce. It is generally defined as an increase ?0.2 ng/ml above the nadir, followed by a spontaneous drop back to nadir or lower. Some definitions allow for a PSA increase up to 2.0 ng/ml. Studies show a wide range of when the bounce begins (roughly 12-24 months) and how long it lasts before it gradually returns to nadir (8 months or more).
What causes the bounce?
A bounce is not automatically bad. In fact, patients who have post-radiation bounce “… have improved PSA recurrence-free survival, distant metastasis-free survival, overall survival, and cancer-specific survival outcomes.”[i] Yet no one knew exactly what causes a bounce, or how to explain how better survival is connected. Theories such as radiation-induced prostatitis (inflammation), variations in lab analysis of PSA, or the destroyed PCa cells shedding PSA into the bloodstream did not add up.
In 2016, a paper by Yamamoto, et al.[ii] established what I believe is a groundbreaking insight into the PSA bounce after brachytherapy: “a strong anti-tumor immune response coupled with the therapeutic effect of radiation on the tumor is responsible for the PSA bounce.” The authors cite previous research showing that the pre-treatment presence of T cells (the “killer” cells of the immune system) within a tumor appears to give a survival advantage to such patients. Cancer cells have their own mechanisms to suppress the immune system. However, for those with a hardy immune system, when the number of cancer cells is slowly diminished by radiation, T cells are “again recruited to the tumor site and perhaps are able to kill more tumor cells leading to the PSA bounce and ultimately, the better outcome.” Thus, the greater the presence of T cells before treatment, the more likely there will be a “significant anti-tumor immune response” when the effects of radiation wear off due to the natural decay of the radioactive isotopes used in brachytherapy. This is why it takes 1-2 years for the bounce to show up.
The team’s theory is further supported by published literature that consistently reports younger patients are more likely to have a PSA bounce than older patients. To that point, the authors suggest that “with aging, the number of tumor-infiltrating T cells decreases.” In other words, younger men are more likely to have robust immunity than older men.
I believe the Yamamoto paper not only helps solve a mystery going back to the 1990s, but is also an important contribution to our understanding of how prostate cancer therapies can be better designed to interface with the body’s own defenses. I can only say, great job!
NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.References
[i] Loos G, Buteau JP, Oh J, Van Dyk S, Chang D, Murphy DG, Hofman MS, Williams S, Chander S. PSMA PET/CT patterns of recurrence after mono-brachytherapy in men with low and intermediate prostate cancer and subsequent management. Brachytherapy. 2024 Oct 1:S1538-4721(24)00113-2.
[ii] Romesser PB, Pei X, Shi W, Zhang Z et al. Prostate-Specific Antigen (PSA) Bounce After Dose-Escalated External Beam Radiation Therapy Is an Independent Predictor of PSA Recurrence, Metastasis, and Survival in Prostate Adenocarcinoma Patients. Int J Radiat Oncol Biol Phys. 2018 Jan 1;100(1):59-67.
[iii] Yamamoto Y, Offord CP, Kumura G, Kuribayashi S et al. Tumour and immune cell dynamics explain the PSA bounce after prostate cancer brachytherapy. Br J Cancer. 2016 Jul 12;115(2):195-202.
About Dr. Dan Sperling
Dan Sperling, MD, DABR, is a board certified radiologist who is globally recognized as a leader in multiparametric MRI for the detection and diagnosis of a range of disease conditions. As Medical Director of the Sperling Prostate Center, Sperling Medical Group and Sperling Neurosurgery Associates, he and his team are on the leading edge of significant change in medical practice. He is the co-author of the new patient book Redefining Prostate Cancer, and is a contributing author on over 25 published studies. For more information, contact the Sperling Prostate Center.
