Bounces after Primary Radiation Therapy

Perhaps the single most annoying "side effect" of radiation 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 Memorial Sloan Kettering 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. The median radiation dose was 81Gy. 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:

• 16% of patients had a bounce
• The bounce occurred after a median of 24.6 months
• It was a 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
• were 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 months vs 26 months) 
• Lower risk of PSA relapse (9% vs 29%)
• Decreased risk of metastases (1% vs 10%)
• Decreased prostate-specific mortality (0% vs 3%)
• Decreased overall mortality (6% vs 11%)

Very similar findings have been reported for other forms of radiation: SBRT, Low Dose Rate Brachytherapy (seeds), High Dose Rate Brachytherapy, and Brachy Boost Therapy. A 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% received > 78 Gy) and because the higher risk men were treated between 1986 to 1995, mostly before PSA testing became prevalent.

The percent of men who experience a bounce ranges from 15%-50%, and depends on how the researchers define a bounce. It ranges from a minimum of  0.1- 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 - either pre-existing, arising after invasive procedures (e.g., biopsy, fiducial placement, or brachytherapy), or 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. However, 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.