Reduction of the PSA level after curative treatment is a hallmark by which treatment success for prostate cancer is defined. In the setting of radical prostatectomy, stably undetectable PSA levels are usually achieved within a few weeks after surgery. This situation is different in the setting of prostate cancer that is treated using non-surgical methods including radiation therapy and HIFU, because measurable PSA levels are almost universally present for an extended period, showing great variability among patients and at different time points. Hence, for definition of successful therapy, the expected course of the PSA level following treatment is a decline to a nadir.
It is generally thought that the PSA level decreases continuously after potentially successful radiation treatment for prostate cancer, and that an increase in the PSA level might reflect disease recurrence. However, prostate cancer patients often show a temporary rise in their PSA levels after radiation therapy. This is known as the “PSA bounce”, which does not reflect disease recurrence.
In the present study, riPSA was defined as an increase ≥0.2 ng/ml with spontaneous return to the prebounce level or lower—the same definition as that used for the PSA bounce. The PSA bounce phenomenon was first recognized in patients receiving combined external beam radiation therapy and permanent prostate implants, and its exact cause is unclear, although suggestions have included radiation therapy-induced prostatitis resulting from compromised membrane integrity. Previous studies have also implicated recent instrumentation such as biopsy, bicycle riding, or recent ejaculation as causes. There are various definitions of the PSA bounce.1–3
Many have defined it as an increase in the PSA level by 0.1%,4
above the nadir. T stage, prostate volume, irradiation dose, hormonal therapy, and age have been reported as predictive factors for the PSA bounce.8
In a recent review, younger age was the only consistent predictive factor.8
Most studies that have examined the PSA bounce have been based on patients who underwent radiation therapy. The onset of PSA bounce after radiation therapy usually occurs during mid-term through long-term follow-up. In patients undergoing permanent implant brachytherapy, the time of onset of the PSA bounce varies from 12 months–24 months depending on the definition.5,9
Although it is believed that the PSA bounce never occurs with HIFU,10
no researchers have yet focused on the PSA increase in the acute phase after HIFU therapy. In our present series, after each treatment, PSA showed a marked increase at 2 days, and accordingly we coined the term “rapid increase of the PSA level” to describe it. To our knowledge, this is the first published study to hav analyzed patients showing a rapid increase of the PSA level after HIFU therapy. Because HIFU is non-ionizing, the cause of this PSA increse may differ from radiation therapy. It can be speculated that ultrasound-induced prostate tissue necrosis may be the histological basis of this phenomenon. At the point where the waves emitted from the HIFU unit are focused, the sudden and intense absorption of the ultrasound beam creates a sudden elevation of temperature (to greater than 85 °C), which destroys the prostate cancer cells located in the target zone. The extremely high intensity of the ultrasound in prostate tissue may itself account for discrete tissue necrosis, a phenomenon that is likely absent after external beam radiation therapy, which in turn can also result in a steep increase of the PSA level. If this riPSA can be regarded as a form of bounce phenomenon, then the time until the bounce is much shorter than that resulting from radiation therapy. PSA kinetics after HIFU may follow a course different from that with other modalities, especially radiation therapy. Unlike radiation, HIFU is an ablation technology, which rapidly increases the temperature, resulting in coagulative necrosis; this means that PSA levels decline quickly after rapid increase of PSA in response to tissue necrosis and take only 3 through 6 months to reach a nadir. For radiation, the behaviour of PSA is more complex. The radiation does not of itself kill cells. Radiation therapy works by damaging the DNA of cells. Generally, this is repairable but sometimes it produces fatal damage so that the DNA damage is inherited through cell division, accumulating damage to the cancer cells, causing them to die or reproduce slowly. The cells with fatally damaged DNA still continue to produce PSA and this only ceases when they die. As a result, PSA declines quite slowly after radiotherapy, showing the marked contrast to HIFU.
Two precipitating factors—lack of hormonal therapy and a higher PSA nadir—were found to increase the risk of riPSA (). Hormonal therapies have a repressive effect on follow-up PSA levels, as might be expected. In our series, 83.5% of patients without hormonal therapy showed the riPSA, compared with 14.1% of patients who received hormonal therapy. Although, neither hormonal therapy nor riPSA showed a significant tendency to be related to biochemical recurrence on univariate analysis (), multivariate Cox regression analysis showed that riPSA and the number of HIFU sessions were predictors of biochemical recurrence (). This provides evidence that riPSA may not automatically dictate hormonal therapy. In our series, log-rank test demonstrated a significant association (P = 0.0354) between the presence of riPSA and the risk of biochemical failure only in the low- and intermediate-risk group (). riPSA may thus be potentially predictive of biochemical recurrence in selected patient populations, especially those with non-high-risk cancer. In our cohort, prognostic value of riPSA was lost in high-risk cancer. This is explainable by the fact that the definition for high-risk group does not account for some adverse variables. High-risk prostate cancer is a quite heterogeneous group that includes patients with clinically locally advanced stage disease at diagnosis, in which some have micrometastatic disese, some have local extension, and some have neither. Hence, high-risk patients with a riPSA after irradiation may be a heterogeneous group, including patients with truly localized failure as well as those with metastatic disease. Further risk stratification within this heterogeneous high-risk group would be useful to assess which patients are most likely to fail HIFU therapy.