The use of PSA as a tumor marker for prostate cancer is widespread and well-studied. The use of total serum PSA to identify patients with prostate cancer has been well-established since the early 1990 s and has resulted in a large increase in the detection of early stage prostate cancer . Serum PSA is now widely used as a marker to determine responses to primary therapy, to monitor responses to hormonal therapy and to detect recurrent cancer.
PSA can be used to determine the efficacy of primary therapy including radical prostatectomy and radiation therapy. The PSA nadir after radical prostatectomy has been shown to correlate strongly with recurrence . Patients treated with external beam radiation therapy quite often still have low but detectable levels of PSA upon completion of their therapy. Those who demonstrate three consecutive increases in PSA are considered to have recurred based upon the American Society of Therapeutic Radiology and Oncology's (ASTRO) definition . Additionally, patients who experience a rise by 2 ng/mL or more above the nadir PSA after external radiation therapy with or without NAAD are considered to have biochemical failure according to the RTOG-ASTRO Phoenix definition .
Similarly, serum PSA can be utilized to determine response to hormonal therapy. Patients treated with androgen deprivation therapy often have dramatically reduced levels of PSA upon completion of their therapy. This decrease in PSA level has been shown to coincide with improved clinical symptoms in prostate cancer patients. Also, a PSA nadir of less than 0.4 ng/mL has been shown to be correlated with the duration of remission .
Our findings point to three distinct factors that appear to be involved in affecting the time to normalization of PSA after treatment for clinically localized prostate cancer with IMRT: tumor stage, Gleason score, and the use of NAAD therapy.
PSA levels normalized below both 2 ng/mL and 1 ng/mL at a much slower rate when the tumor being treated was a stage T2 tumor rather than when the tumor was stage T1 or T3. Patients with stage T2 tumors had an average time to normalization of 95 days longer than patients with stage T1 tumors and 221 days longer than patients with stage T3 tumors when normalizing to PSA < 2 ng/mL. Similarly, patients with stage T2 tumors had an average time to normalization to PSA < 1 ng/mL of 111 days longer than those with stage T1 tumors and 286 days longer than those with stage T3 tumors.
The difference in time to normalization of PSA < 2 ng/mL between stages T1, T2, and T3 was statistically significant. It could be hypothesized that those patients with stage T2 disease possess a different biologic phenotype that reacts more rapidly to androgen deprivation. It may be true that stage T3 cancers are more dispersed so as to allow a greater interaction between those malignant cells that make up the tumor and the circulating anti-androgen affects of the therapy. With a more extensive and richer connection to systemic blood supplies, the stage T3 tumor may also be more susceptible to the effects of the androgen deprivation therapy. Alternatively, potentially being more de-differentiated, T3 tumors may respond more rapidly to NAAD.
The T1 tumors also show a relative susceptibility to PSA normalization in comparison with T2 tumors. There is potentially a different explanation as to why they are more susceptible. Having less tumor burden, there is potentially a greater chance that T1 patients will undergo apoptotic cell death due to androgen deprivation to cause a significantly faster normalization of PSA level. The T2 tumors may have invaded to the point that a certain percentage of malignant cells will simply be untreated by the affects of androgen deprivation, but have not invaded to the point where their increased access to the systemic blood supply results in greater susceptibility to the anti-androgen affects of the therapy. Overall, it is difficult to make definitive conclusions regarding T stage and rate of PSA normalization, as only 5% of our sample had T3 disease and 15% had T2 disease.
Our data also showed a statistically significant correlation between the Gleason score of a tumor and the rate of PSA normalization to below 1 ng/mL, but not to below 2 ng/mL. This may possibly be explained by the fact that the cells that comprise a tumor with a high Gleason score are, by definition, less differentiated. It has been well documented that tumors of a higher Gleason score are made up of cells that actually produce less PSA per cell [13, 14]. It then would follow that androgen deprivation therapy could very well have a more profound impact on the PSA production abilities of cells that were already less differentiated.
Finally, our data demonstrate that patients treated with IMRT plus NAAD normalized to a serum PSA level below 1 ng/mL 102 days earlier than those patients treated with IMRT alone. This effect was not significant when the level of PSA normalization was set at less than 2 ng/mL. It is possible that the use of NAAD therapy acts as a radiosensitizer in areas of the tumor mass. It is also possible that the androgen deprivation therapy is causing apoptotic cell death, as well as surviving tumor cells to cease production of PSA.
When androgen deprivation therapy is implemented, there is a subsequent apoptotic death of large numbers of cancerous prostate cells. This results in a significant decrease in the serum PSA level due to decreased prostatic cell mass. However, it has been shown that because transcription of the PSA gene is regulated by an androgen receptor, not all of this serum PSA decrease is due to cell death. Some surviving tumor cells are simply blocked from producing PSA because of the lack of androgen available to stimulate transcription of the PSA gene [15, 16]. This phenomenon may also explain in part the significantly shorter time to PSA normalization when androgen deprivation therapy is combined with IMRT.
Serum PSA levels are routinely used today as a measure of a therapy's impact on prostate cancer. With such a significantly quicker normalization of PSA when neoadjuvant hormone therapy is used in conjunction with IMRT, this may constitute a reason to think more seriously about expanding the role of NAAD therapy in these patients. Further study is needed to elucidate whether the rate of PSA normalization is linked to notable endpoints such as mortality or disease recurrence. If it is found that a faster rate of PSA normalization to a level below 1 ng/mL is associated with decreased mortality or disease recurrence rates, then the use of NAAD therapy may need to be expanded to men with clinically localized disease.
Some work in this area has been done with some conflicting results. In a very large study that showed the importance of PSA normalization, Collette et al. assessed whether PSA could serve as a surrogate endpoint for survival . They showed that, using a PSA normalization value of 4 ng/mL, those patients who normalized showed 4.9-fold greater odds of surviving than those patients who did not normalize. While this does not directly attest to the importance of the rate of PSA normalization, given the nearly 5-fold greater odds of survival for those patients achieving normalization, achieving that goal would be of significance.
Of additional concern is whether reduced time to PSA nadir is related to more positive outcomes. Chung et al. noted that, for PSA nadir values > 0.9 mg/mL, increased time to PSA nadir was associated with increased prostate cancer specific mortality and all causes mortality, relative to men with a time to PSA nadir < four months . Conversely, both Ray et al. and Hori et al. have shown a direct relationship between positive outcomes and a decreased time to PSA nadir [19, 20]. In our cohort, we did not correlate time to PSA normalization with clinical outcome.
Additionally, our data showed no significant relationship between the rate of normalization of PSA and the duration of NAAD therapy. Previous studies have attempted to determine the optimal duration of androgen deprivation therapy for men with clinically localized prostate cancer. One large study by Crook, et al. showed no difference in overall survival, disease-free survival, or rates of recurrence between two groups of men with clinically localized prostate cancer treated with either 3 or 8 months of neoadjuvant androgen deprivation therapy . The same study, however, did show a difference in disease free survival among men with high risk disease. A number of other studies have also shown that, at least in men with high risk clinically localized disease, there may be significant benefits to a longer duration of androgen deprivation therapy [22, 23]. Overall, studies have shown conflicting results in terms of whether the duration of androgen deprivation therapy has any true effect on mortality and disease recurrence rates.