PSA “bounces” after first-line radiation therapy

Perhaps the single most annoying “side effect” of radiation therapy for prostate cancer is not a side effect at all; it’s the periodic fluctuations in PSA, called “bounces,” that can occur for years after therapy. A new analysis from researchers at the Memorial Sloan-Kettering Cancer Center assures us that our anxiety is misplaced — PSA bounces predict better cancer control.

Romesser et al. reported on a retrospective study among 776 patients treated from 1990 to 2010 with dose-escalated external beam radiation therapy (EBRT). The median radiation dose was 81 Gy. None received adjuvant ADT. They defined a bounce as a PSA rise ≥ 0.2 ng/ml but less than 2.0 ng/ml above the lowest level (nadir) it had reached thus far, followed by a decrease to as low or lower than the previous nadir. After a median follow-up of 9.2 years, they found that:

  • 16 percent of patients had a bounce.
  • The bounce occurred after an average (median) of 24.6 months.
  • It was an average (median) of 0.37 ng/ml over the previous nadir.

Bounces were more likely to occur in patients who:

  • Were younger (see this link)
  • Had a lower Gleason score
  • Had a lower T stage
  • Received a higher radiation dose

At 8-years follow-up, they reported that bounces were associated with:

  • Greater time to reach ultimate PSA nadir (43 vs 26 months)
  • Lower risk of PSA relapse (9 vs 29 percent)
  • Decreased risk of metastases (1 vs 10 percent)
  • Decreased prostate-specific mortality (0 vs 3 percent)
  • Decreased overall mortality (6 vs 11 percent)

Very similar findings have been reported for other forms of radiation, including: SBRT, low-dose-rate brachytherapy (seeds), high-dose-rate brachytherapy, and brachy boost therapyA 2004 study of EBRT and bounces found an inverse correlation between bounces and PSA relapse-free survival. The difference is probably attributable to much lower radiation dose (only 1 percent received > 78 Gy) and because the higher-risk men were treated between 1986 to 1995, mostly before PSA testing became prevalent.

The percentage of men who experience a bounce ranges from 15 to 50 percent and depends on how the researchers define a bounce. It ranges from a minimum of 0.1 to 0.8 ng/ml above previous nadir in most studies. Bounces are often above +1 ng/ml, may last for more than a year, and are usually noted between 1 year and 4 years after therapy.

The reason that bounces occur is a bit of a mystery. There are various theories:

  • Prostatitis — which may be pre-existing, can arise after invasive procedures (e.g., biopsy, fiducial placement, or brachytherapy), or can be induced by radiation.
  • Immune infiltration: after radiation releases cancer antigens, T cells are activated to eventually attack the remaining cancer in the prostate (see this link).
  • Cancer cells that have been dormant, eventually emerge and undergo mitotic catastrophe.
  • Delayed apoptosis (cell death) among late-responding healthy cells
  • PSA drops most sharply and consistently in more aggressive cancers because radiation kills the most rapidly dividing cells first.
  • PSA measurement variation (e.g., different test kits, different labs, natural fluctuations)

Whatever the reason, bounces are a good thing. For patients that were diagnosed with low- or intermediate-risk prostate cancer, a slow, bouncy PSA decline should engender a feeling of relief rather than anxiety. But what of the unfavorable-risk patient with bounces so high that they approach or exceed +2.0 ng/ml and stay elevated? While recurrences usually occur later than bounces, is there a method available for early detection of a local recurrence? Biopsies are invasive and non-informative while the cancer is still in the “slow death” phase. There is a kind of MRI called MR spectroscopy (MRS) that may be able to non-invasively distinguish between bounces and PSA recurrence. In a pilot study (and this one), the researchers found that the MRS-detected choline/citrate ratio might be markedly elevated and focal if the cancer is metabolically active, but low and diffuse if there is only benign inflammatory activity.

Editorial note: This commentary was written by Allen Edel for The “New” Prostate Cancer InfoLink.

2 Responses

  1. Excellent information; really helpful insight for patients considering radiotherapy; and an important “read” for support group leaders and other advocates and educators. Thanks Allen!

  2. Thanks, and combing data for a paper involving metformin?

    Thanks Allen for another most helpful report!

    I think of the group behind this study as the Zelefsky group as he is the senior author and so well known for his wonderful pioneering leadership in radiation for prostate cancer. In 2013 that group’s study of metformin’s association with stunningly superior results after radiation was published. I just looked over the population details for both this bounce study and the metformin study, and it looks like there would be substantial overlap. We may never see it, but it would be interesting to see the bounce results looked at in the context of metformin use. In these days of electronic databases, that would probably not be hard to do.

    Of course, drawing the line on what to include can be difficult. Do you filter for age group, modern radiation dosing, image-guided radiation, etc. in addition to bounce and metformin use?

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