External beam radiotherapy for stage T1/T2 prostate cancer: how does it stack up?

Objectives. To determine the impact of radiation dose on the response of Stage T1/T2 prostate cancer to external beam radiation therapy and to contrast the modern-day clinical and biochemical control rates to those seen after radical prostatectomy or permanent iodine-125 seed implants. Methods. The study cohort consisted of 643 patients with palpable Stage T1/T2, NX/N0, M0 prostate cancer treated with external beam radiotherapy between 1987 and 1995. No patient received neoadjuvant or adjuvant androgen ablation. The radiotherapy isocenter dose ranged from 60 to 78 Gy, with a mean of 67 and a median of 66. Median follow-up was 43 months. The primary end point was freedom from relapse or rising prostate-specific antigen (PSA) level. Results. The patients were divided into two dose groups with the cutpoint based on the mean and median values, and prior analyses. There were 354 patients treated to radiation doses of 67 Gy or less and 289 treated to doses greater than 67 Gy. Those receiving the higher doses had a significantly greater 4-year freedom from failure rate of 87% versus 67% ( P < 0.0001). Multivariate Cox proportional hazards analyses revealed that isocenter dose was independent of Gleason score and pretreatment PSA level, which were the other significant covariates. Conclusions. Very high freedom from failure rates were achieved when the radiation dose to the prostate was above 67 Gy. These rates are promising when compared to published radical prostatectomy series and most permanent iodine-125 seed implant series in which patients were stratified by pretreatment PSA. Further follow-up is needed to confirm that these promising results are sustained

The fall and rise of prostate‐specific antigen: Kinetics of serum prostate‐specific antigen levels after radiation therapy for prostate cancer

Background. The serum kinetics of prostate‐specific antigen (PSA) after radiation therapy for prostate cancer are not well characterized, and the potential prognostic significance of serum half‐lives and of serum doubling times is unclear. This study was designed to address those issues. Methods. One hundred fifty‐four patients with at least four serial PSA determinations who received external‐beam radiation therapy alone were analyzed to determine PSA kinetics and to correlate kinetic parameters with outcome. Nonlinear regression techniques were used to estimate PSA half‐lives and doubling times. Results. The PSA data fitted well to exponential models consistent with the hypothesis that PSA kinetics after radiation follow first‐order (exponential) kinetics. The mean PSA half‐life was 1.9 months (range, 0.5 to 9.2 months). No significant correlation existed between half‐life and grade, stage, acid phosphatase level, serum testosterone level, or patient age. A weak correlation between half‐life and pretreatment PSA level was observed: patients with low PSA levels tended to have longer half‐lives. Half‐life did not correlate with disease relapse or with the likelihood of developing a rising PSA profile. PSA doubling time in 37 patients with rising values ranged from 1.6 to 53 months (mean, 12.5 months). Doubling times were significantly longer than half‐lives by an average factor of 6.5 and there was no correlation between half‐life and subsequent doubling time. Doubling times were longer in low‐grade tumors. Conclusions. Serum kinetics of PSA in particular its rate of fall after radiation provide little, if any, useful clinical information. It is possible that serum kinetics of PSA are related to tumor cell kinetics but such relationships remain speculative. Correlative cell kinetic—PSA kinetic studies are needed to elucidate the mechanisms underlying the changes in PSA level after radiation therapy

The serum prostate-specific antigen level three months after radiotherapy for prostate cancer: an early indicator of response to treatment

A total of 347 patients with stages A2-C adenocarcinoma of the prostate treated with external beam radiotherapy and with pretreatment and 3-month prostate-specific antigen (PSA) levels were studied to evaluate the potential prognostic significance of the fall in PSA concentration from its baseline (PSAB) to its 3-month (PSA3) level. PSA levels fell in 333 patients (96%). With two exceptions, the patients whose PSA level did not fall had low PSAB and remained without evidence of disease. Since PSA levels fall virtually always, the fact that a fall occurs is of no prognostic value. When the magnitude of the fall relative to baseline was examined, patients with the largest falls had the worst outcomes. This paradoxical result was explained by the relationship between PSAB and PSA3. Regression analysis showed that the fall in PSA level was approximately proportional to the cube root of the baseline value. Thus, patients with high PSAB had high falls, but a high PSAB was an ovewhelming predictor for poor outcome. Hence, PSA fall relative to baseline was not a meaningful prognostic factor. The only factor of prognostic value was the absolute PSA3 value. Patients with PSA3 ≤2 ng/ml fared well at 4 years (freedom from relapse, 91%; incidence of rising PSA profile, 20%); patients with PSA3 > 2, but 10 ng/ml can be said to have failed treatment (freedom from relapse, 50%; incidence of rising PSA profile, 90%). Although this analysis is based on short follow-up, it shows that the PSA value at 3 months after radiation provides a remarkably early assessment of response to treatment and the only patients who can be clearly stated to have responded well to treatment are those whose PSA level falls to ≤ 2 ng/ml. The long-term implications of 3-month PSA values await further follow-up

Androgen ablation in addition to radiation therapy for prostate cancer: Is there true benefit?

Prostate cancer patients may now be identified as having a high risk of failing single-modality treatment based on pretreatment prostate specific antigen (PSA), Gleason score, and palpable stage. In particular, a PSA greater than 20 ng/mL portends a biochemical failure rate of 50% to 80% when radiation therapy, surgery, or androgen ablation is administered individually. A number of randomized trials as well as retrospective data show that failure rates are significantly reduced by combining androgen ablation and radiation. The improved results, however, are complicated by the ability to salvage radiation alone-treated patients with androgen ablation and the possibility of less effective salvage (or no effective salvage in the case of permanent androgen ablation) for patients treated with androgen ablation plus radiation. Thus, survival, which is obscured by high rates of intercurrent deaths in this elderly population, is the most important end point in such studies. Two randomized trials, one from the Radiation Therapy Oncology Group (RTOG) and one from the European Organization for Research on Treatment for Cancer (EORTC), of radiation therapy plus adjuvant (as opposed to neoadjuvant) androgen ablation have reported survival gains over radiation therapy alone. In contrast, one neoadjuvant trial from the RTOG failed to show a survival benefit when androgen ablation was added to radiation therapy. In this study, however, androgen ablation was administered for only 4 to 5 months, which may be insufficient. The weight of the evidence to date indicates a true benefit with androgen ablation plus radiation therapy over radiation therapy alone. There are clearly many unanswered questions concerning the optimal timing of androgen ablation and radiation therapy (neoadjuvant versus adjuvant), length of time that androgen ablation should be administered (6 months versus 3 years versus permanent), type of androgen ablation (total androgen ablation or not), and appropriate patient population (definition of high risk). The planned future clinical trials will address many of these issues; however, the full potential of this approach requires an understanding of the fundamental mechanisms involved

Serum testosterone levels after external beam radiation for clinically localized prostate cancer

Purpose : To determine whether serum total testosterone levels change after external beam radiation therapy for localized prostate cancer. Methods and Materials : Eighty-five men with clinically localized prostate cancer (T1–T3, N0/NX, M0) who underwent external beam radiation therapy without androgen ablation had pretreatment and 3-month posttreatment total serum testosterone levels determined by radioimmunoassay. Scattered doses to the testicles were measured with thermoluminescent dosimetry in 10 men. Results : Pretreatment serum testosterone levels ranged from 185 to 783 ng/dl, with a mean of 400 ng/dl and a median of 390 ng/dl. THe coefficient of variation was 30%. Postradiation 3-month testosterone levels ranged from 163 ng/dl to 796 ng/dl, with mean and median values of 356 ng/dl and 327 ng/ml, respectively. The coefficient of variatioin was 34%. The 3-month value was significantly lower than the pretreatment value (Wilcoxon paired p = 0.0001). The mean absolute fall was 94 ng/dl and the mean percentage fall was 9%. Although the fall in testosterone level was statistically significant, the difference was very small quantitatively. In contrast, serum prostate-specific antigen levels fell dramatically by 3 months after radiation. Testicular scattered does ranged from 1.84 to 2.42 Gy, with a mean of 2.07 Gy for a prostatic tumor dose of 68 Gy. Conclusions : Although significant, the fall in serum testosterone level after radiation for localized prostate cancer was small and likely of no pathophysiologic consequence. It is unlikely that scattered testicular radiation plays any significant role in the genesis of this change in testosterone level, which most likely occurs as a nonspecific stress response

Kinetics of serum prostate-specific antigen after external beam radiation for clinically localized prostate cancer

Background and purpose: To determine the kinetics of serum prostate-specific antigen (PSA) after radiation therapy of localized prostate cancer and to evaluate whether such kinetics provide prognostic information. Materials and methods: Eight hundred forty-one men with serial PSA determinations who underwent external beam radiation without androgen ablation were analyzed to determine postradiation PSA kinetic parameters (half-life and doubling time) and to correlate these parameters with disease outcome. Non-linear regression techniques were used to determine half-lives and doubling times. Results: The postradiation serum PSA data fitted well to first order kinetic models. The median PSA half-life was 1.6 months (range 0.5–9.2 months). There was no correlation between half-life and T-stage or Gleason grade. A significant but quantitatively weak correlation was present between the pretreatment PSA level and half-life; lower pretreatment levels were associated with longer half-lives. Half-life did not correlate with disease outcome whether the endpoint was local recurrence, distant metastasis or rising PSA. In 263 men with a rising postradiation PSA profile the median PSA doubling time was 12.2 months (range 0.8–80.2 months). Faster doubling times were significantly associated with higher T-stage, higher Gleason grade and higher pretreatment PSA levels. Thus, patients with initially adverse disease developed faster rising PSA values after treatment than patients with less adverse disease. The most striking correlation was between rapid doubling time and the likelihood of metastatic relapse. Patients who developed metastases had a median PSA doubling time of 4.2 months compared to a median doubling time of 11.7 months in patients who developed local recurrence. Overall, patients with a PSA doubling time of less than 8 months had a 7-year actuarial metastatic rate of 54%, while patients with a PSA doubling time exceeding 8 months had only a 7% metastatic rate. Particularly ominous was the combination of a doubling time shorter than 8 months which began to rise within the first year; by 3 years 50% of these men had metastases and all were actuarially projected to develop such relapse by 6.5 years. Conclusions: Overall, the clinical utility of postradiation serum PSA kinetics was small. There were no discernible uses for PSA half-life. In patients with a rising PSA profile the faster the kinetics the more adverse the disease. Doubling times shorter than 8 months, especially if the rise begins in the first year, predict for metastatic relapse. However, in the absence of decisively useful treatment for metastatic prostate cancer the virtues of the early detection of metastases remain unclear