PSA-related parameters in prostate cancer relapsed after endocrine therapy

PURPOSE: Prostate cancer is generally controlled by endocrine therapy even in an advanced state, but relapse may occur in many cases. Generally, the prognosis of a relapsed case is poor, but the prognosis differs case by case. We experienced 74 cases of prostate cancer relapsed after effective endocrine therapy, and investigated the relationship between the PSA-related parameters, clinical stage and prognosis. PATIENTS AND METHODS: We investigated 74 prostate cancer patients whose PSA declined 10 ng/ml or lower by the treatment consisting of endocrine therapy, but relapsed later. Pre-treatment PSA, the value of PSA nadir, the period from the start of treatment to PSA nadir, the period from the start of treatment to relapse, PSA doubling time (PSA-DT) at relapse and PSA response to the second line therapy at relapse were calculated, and compared with the clinical stage and prognosis. The relationship between each PSA parameter and clinical stage was tested using the Kruskal-Wallis test and chi 2 test. Cancer-specific survival after relapse in stage D patients was calculated by the Kaplan-Meier method and differences in prognosis were tested using the Logrank test. RESULTS: Pre-treatment PSA was significantly (p < 0.01) high, while the period from the start of treatment to relapse (p < 0.05) and PSA-DT at relapse (p < 0.01) was significantly short as the stage progressed. According to PSA response to the second line therapy at relapse, the rate of CR + PR was significantly (p < 0.05) high in clinical stage B + C group compared to clinical stage D group. The prognosis after relapse was significantly poorer in patients with relapse within 10 months after start of treatment than in those with relapse later, and in patients whose PSA-DT at relapse was shorter than 2 months than in those with a longer PSA-DT. CONCLUSIONS: The period from the start of treatment to relapse, and PSA-DT at relapse were useful PSA-related parameters for predicting prognosis after relapse, and for determining the strategy of cancer therapy after relapse. Using these data, the physician can inform the family and the patient of the prognosis more accurately, so that they can adjust future plans.     

Prognostic factors for PSA relapse of prostate cancer after endocrine therapy

PURPOSE: Advanced prostate cancer responds well to endocrine therapy initially, but soon becomes refractory and has a poor prognosis. We analyzed the prognostic factors of prostate cancer responding well initially to endocrine therapy with lowering of serum prostate specific antigen (PSA) level but later showing PSA relapse. MATERIALS AND METHODS: In prostate cancer patients newly diagnosed from January 1992 to December 2004 at our institution, there were 93 patients in that the PSA level of 10 ng/ml or more before therapy initially dropped below 10 ng/ml by endocrine therapy, but showed PSA relapse thereafter. We investigated the relationship between clinical stage, pathological differentiation, initial PSA, duration between initiation of therapy and PSA nadir, the value of PSA nadir, duration between initiation of therapy and PSA relapse, PSA doubling time (PSA-DT) at relapse, PSA response three months after initiation of second line therapy and prognosis after PSA relapse. RESULTS: In Kaplan-Meier method, between all or some categories investigated showed significant difference in prognosis after PSA relapse. In multivariate analysis, the factors that significantly affected prognosis after PSA relapse were clinical stage, pathological differentiation, PSA nadir value, duration between initiation of therapy and PSA relapse and PSA response three months after initiation of second line therapy. CONCLUSION: We investigated the prognostic factors refractory to endocrine therapy. These results are useful in planning the therapy, and in explaining the status or future prospective of the disease to patients and families.     

Prostate-specific antigen in patients with relapsed prostate cancer following endocrine treatment

We assessed the relationship between changes in PSA and prognosis, as a possible reflection of tumour growth in patients who relapse following primary endocrine therapy. In 8 patients in whom no therapeutic change was attempted after PSA relapse, the PSA level increased exponentially. Their PSA-DT had a close positive relation-ship to the duration of survival after relapse (r=0.79, p=0.02). In 6 patients who received chemotherapy after relapse, PSA-DT between PSA relapse and initiation of chemotherapy also had a relationship to the duration of survival after relapse (r=0.87, p=0.05). It appears to be reasonable to conclude from these findings that the PSA-DT value is regarded to be a factor associated with prognosis in cases with an exponential increase in PSA after relapse.     

Utility of prostate specific antigen doubling time in repeat biopsy for prostate cancer

PURPOSE: It is not rare that the repeat biopsy is performed when the initial biopsy was negative. However, there is not a clear indication for the repeat biopsy. We evaluated the utility of prostate specific antigen doubling time (PSA-DT) as indication for the repeat biopsy. MATERIALS AND METHODS: Of men 103 underwent repeat biopsy after initial negative prostate biopsy, 55 men who had three or more serial PSA measurements until repeat biopsy were evaluated. PSA-DT was calculated using a log-linear regression model and compared with other PSA-related parameters. RESULTS: Prostate cancer was diagnosed in 22 patients (40.0%). Mean PSA-DT in 55 patients was 59.3 months. Comparing of repeat positive biopsy group and negative group, PSA density (PSAD) and PSA velocity (PSAV) in the positive biopsy group were significantly greater than in the negative biopsy group. Age, serum PSA concentration at initial and repeat biopsy, PSA adjusted for volume of transition zone (PSATZ), free to total PSA ratio (%F/T) did not recognize significant differences between both biopsy groups. PSA-DT of positive biopsy group (35.1 months) was significantly shorter than that of negative biopsy group (76.5 months). None was diagnosed prostate cancer whose PSA-DT was longer than 96 months. CONCLUSION: When we considered prostate repeat biopsy, it was thought that PSA-DT could be one important material, but it was limitation for indication as to other PSA-related parameters.     

Global update on defining and treating high-risk localized prostate cancer with leuprorelin: a USA perspective--identifying men at diagnosis who are at high risk of prostate cancer death after surgery or radiation therapy

Prostate-specific antigen doubling time (PSA-DT) after surgery or radiotherapy (RT) is known to be a predictive factor for death from prostate cancer (prostate cancer-specific mortality, PCSM). An analysis of two multi-institutional databases, including 8669 men with prostate cancer treated with surgery or RT, found that a PSA-DT of <3 months, and the specific value of the PSA-DT when > or = 3 months, appeared to be surrogate endpoints for PCSM after surgery or RT. While many PSA failures occur after local therapy for localized prostate cancer, few of these patients go on to die from their disease, so it is important to identify other factors associated with PCSM, so that the subgroup of high-risk patients can be identified. An analysis was undertaken to determine whether patients at risk of PCSM could be identified using information available at diagnosis. The results showed that risk factors for PCSM were a PSA velocity of >2.0 ng/mL/year, a Gleason score of 8-10 and an increasing PSA level. However, the most important risk factor that had an impact on both PCSM and all-cause mortality was a PSA velocity of >2.0 ng/mL/year. PSA kinetics are being increasingly used in the setting of rising PSA levels after radical prostatectomy or RT, and several studies showed that the rate of increase in PSA level at the time of recurrence is closely associated with time to cancer death. A PSA-DT of <3 months is associated with a poor prognosis, and represents 15-20% of PSA failures in the general population and 6-7% of PSA failures in a screened population, such as those included in clinical trials. Better risk-assessment models are needed to help to identify at an early stage men who are at high risk of prostate cancer death and those who are at low risk, so that each subgroup can receive the most appropriate therapy for their disease.     

Prostate-specific antigen doubling time among Japanese men in an annual health screening program

BACKGROUND: Prostate-specific antigen doubling time (PSA-DT) has been studied as a parameter reflecting the biological doubling rate of clinically localized prostate cancer treated expectantly. With the use of PSA-DT, we studied the natural history of PSA changes among Japanese men in a health screening program. METHODS: Between July 1994 and December 2002, a cohort of 1995 men aged 40-79 years underwent a total of 5700 PSA measurements in an annual multiphasic health screening program. Prostate-specific antigen doubling time was calculated using a log-linear regression model for 994 (49.8%) men who had three or more serial PSA measurements with a mean follow-up of 46.2 months. RESULTS: Of the 994 men, 192 (19.3%) had a PSA-DT of less than 10 years and 12 (1.2%) had a PSA-DT of less than 2 years. Median PSA-DT in 14 men with a subsequent diagnosis of prostate cancer was 41.6 months (range, 12.2 to stable). A log-linear model statistically fitted 65 of 180 non-cancer patients with a PSA-DT of less than 10 years. The percentages of statistically fit cases increased with higher baseline PSA (5.3%, 7.7% and 8.7% among men with <1.0, 1.0-1.99 and 2.0-3.99 ng/mL, respectively) and older baseline age (3.7%, 8.5% and 6.9% among ages 40-49, 50-59 and 60 or older, respectively). CONCLUSION: In a small but significant portion of men, PSA increases exponentially when it is still less than 4.0 ng/mL, with a PSA-DT of less than 10 years. The clinical significance of this finding should be evaluated by a prospective screening including biopsy.     

Progression after docetaxel-based chemotherapy in androgen-independent prostate cancer

OBJECTIVE: To assess the clinical pattern of progression and prostate-specific antigen doubling time (PSA-DT) after exposure to docetaxel-based chemotherapy in patients with androgen-independent prostate cancer (AIPC). PATIENTS AND METHODS: Fifty-five patients received docetaxel-based chemotherapy; data were collected retrospectively from three different departments. Progression was known in 44 (79%) and the PSA-DT was available in 33 patients. RESULTS: Of the 29 patients with soft-tissue and soft-tissue plus bone metastases, 22 (76%) developed soft-tissue progression. Among the 35 patients with bone and bone plus soft-tissue metastases, 27 (77%) had osseous progression. There was no difference between the PSA-DT at progression before and after docetaxel-based therapy (mean 3.1 vs 2.7 months, P = 0.592, Student's t-test.). However, the median (range) PSA-DT at progression after docetaxel-based therapy was 0.84 (0.3-4) months in patients with a PSA response, significantly shorter than the median of 3.1 (0.3-12) months of patients with no biochemical response (P = 0.002, Student's t-test). The PSA-DT dynamics at progression had no effect on survival (P = 0.63, log-rank test). CONCLUSION: The pattern of progression after docetaxel-based chemotherapy is predominantly osseous in patient with bone metastases and mostly soft-tissue in those with soft-tissue disease. Progression after docetaxel-based chemotherapy in AIPC does not modify the PSA-DT before docetaxel. Evaluation of a larger population is needed to assess the clinical relevance of PSA dynamics after docetaxel therapy.     

Deferred combined androgen blockade therapy using bicalutamide in patients with hormone-refractory prostate cancer during androgen deprivation monotherapy

OBJECTIVE: To assess the effect of adding bicalutamide on serum prostate-specific antigen (PSA) levels in patients with hormone-refractory prostate cancer (HRPC) during androgen deprivation monotherapy (ADMT). PATIENTS AND METHODS: Forty-four patients with HRPC were treated with deferred combined androgen blockade (CAB) therapy, administering bicalutamide 80 mg once daily. HRPC was defined biochemically as three consecutive rises in PSA level during ADMT. The treatment response was defined as a > or = 50% decline in PSA levels. Prognostic values of various pretreatment variables for responsiveness to deferred CAB were determined statistically. When the disease relapsed during deferred CAB, bicalutamide was discontinued and the patients were evaluated for the antiandrogen withdrawal syndrome (AWS). RESULTS: Of the 44 patients, 29 (66%) had a PSA response; the median PSA failure-free survival was 9.2+ months. Biopsy Gleason score was the only pretreatment variable predictive of a PSA response (mean Gleason score 7.9 in responders and 8.7 in nonresponders). The PSA doubling time (PSA-DT) was the only statistically significant variable of PSA failure-free survival in a multivariate analysis. The 1- and 2-year PSA failure-free survival rates were 43% and 31% in patients with a PSA-DT of >4 months, while it was 21% and none, respectively, in those with a PSA-DT of <4 months. Responders to deferred CAB had a statistically longer cancer-specific survival than nonresponders. None of 20 patients who were evaluated for AWS had the condition. CONCLUSIONS: Deferred CAB therapy using bicalutamide is effective in patients with progression during ADMT, particularly in those with lower Gleason score tumours or a longer PSA-DT. AWS after deferred CAB is uncommon.     

Usefulness of extension of disease as a prognostic factor in relapsed prostate cancer patients of stage D

OBJECTIVE: The prognosis of prostate cancer has been evaluated by clinical stage or pathological grade. PSA parameters including PSA density and PSA doubling time have not always precisely reflected the prognosis of prostate cancer. The aim of this study was to evaluate PSA parameters and extension of disease (EOD) grade as prognostic factors for relapsed prostate cancer. METHODS: The relationship between PSA parameters or EOD grade, and survival of 29 stage D patients with relapsed prostate cancer after initial hormone therapy was examined. RESULTS: Only EOD grade was an independent prognostic factor, even for cause-specific survival period and survival period after relapse. CONCLUSION: EOD grade was a significant prognostic factor, and in particular, very useful as a prognostic factor for patients with bone metastasis. PSA value was not always associated with tumor volume, and therefore it is not an independent prognostic factor.     

Early results of radical prostatectomy and adjuvant endocrine therapy for prostate cancer with or without preoperative androgen deprivation

Background : The effects of preoperative androgen deprivation were explored in the patients who received radical prostatectomy and subsequent adjuvant endocrine therapy for prostate cancer.
Methods: Stage A₂, B or C prostate cancers were randomized to one of two groups: (i) group I ( n = 90), who received androgen deprivation (leuploride and chlormadinone acetate) for 3 months preoperatively followed by radical prostatectomy and adjuvant endocrine therapy (leuploride only); and (ii) group II ( n = 86), who underwent the surgery followed by 3 month androgen deprivation and subsequent adjuvant endocrine therapy. The effects of preoperative androgen deprivation on clinical relapse (serum prostate specific antigen (PSA) > 1.98 ng/mL, local recurrence or distant metastasis) and PSA relapse (PSA > 0.2 ng/mL) were evaluated at 2 years after randomization.
Results: There was no significant difference in clinical or PSA relapse-free survival and quality of life measures between the two groups, although relapses occurred significantly more frequently in patients who had more advanced stages, higher pretreatment PSA values or lower histologic differentiation in either group. Subgroup analysis indicated that clinical relapse-free survival in stage C cancer tended to be better in patients with preoperative androgen deprivation than in those patients without it ( P < 0.1).
Conclusions : Preoperative androgen deprivation may be beneficial for stage C prostate cancer patients receiving radical prostatectomy and adjuvant endocrine therapy over the 2 year observation period. A longer follow up is needed to clarify the exact extent of benefit in terms of survival and quality of life.     

Correlation of initial PSA level and biopsy features with PSA-doubling time in early stage prostate cancers in Japanese men

OBJECTIVE: To distinguish good candidates for watchful waiting from those who need immediate treatment in localized prostate cancer. METHODS: Prostate specific antigen (PSA)-doubling time (DT) was calculated by a log-linear regression model for 78 patients with clinically localized prostate cancer (T1c: 47, T2a: 6, T2b: 21, and T3: 4) under surveillance. Median observation period was 37.5 months. The first 1-year PSA-DT was compared with the overall PSA-DT in 41 patients who had been under surveillance for more than 3 years. RESULTS: There was significant difference in the PSA-DT distribution between a pooled group of T1c and T2a and a group of T2b and T3 patients (median 58.8 versus 33.3 months, P = 0.0052). A combination of three parameters consisting of initial PSA level less than 10 ng/ml, WHO grade 1, one or two positive core per six to eight systematic biopsy cores with 50% or less cancer involvement significantly correlated with PSA-DT distribution in the T1c plus T2a group (P = 0.0034). The first year assessment of PSA-DT was identical to the overall assessment in 48.8%, 2 years or more in 36.6%, while it was 2 years or less (possibly over-estimated) in 14.6%. CONCLSION: PSA-DT can be predictable to some extent with the initial PSA level and biopsy features in early stage prostate cancers. Prospective study is needed to clarify whether temporary observation together with PSA-DT estimation is a safe strategy and is complementary to clinico-pathological parameters at diagnosis.     

Response to second-line hormonal manipulation monitored by serum PSA in stage D2 prostate carcinoma.

Changes in prostate-specific antigen (PSA) have been demonstrated to accurately assess response to initial hormone deprivation in metastatic prostate cancer patients. The role of PSA in monitoring response to second-line hormonal treatment has not been documented. In a group of 20 patients with an initial response to androgen deprivation and subsequent relapse, we monitored PSA levels before and after second-line therapy. Ten patients had a clinical response. Four had a more than 90 percent decrease in serum PSA compared with the level at initial progression. This clinical response was maintained for a mean of eighteen months. Six patients had a PSA decrease less than 90 percent; their clinical response was of a mean 5.5 months. Ten patients had no change or increase in PSA. Seven had no clinical response, and 3 responded for an average of four months. Although production of PSA might be under endocrine control, changes in PSA are useful for monitoring response to second-line hormonal therapy.     

Radical prostatectomy and adjuvant endocrine therapy for prostate cancer with or without preoperative androgen deprivation: Five-year results

BACKGROUND: The effects of preoperative androgen deprivation on the outcomes of prostate cancer patients who received radical prostatectomy and subsequent adjuvant endocrine therapy have not yet been fully evaluated. METHODS: Patients with stage A(2), B or C prostate cancers were randomized to one of two groups: group I (n = 90), who received androgen deprivation (leuprolide and chlormadinone acetate) for 3 months followed by radical prostatectomy and subsequent adjuvant endocrine therapy (leuprolide alone), and group II (n = 86), who underwent the surgery followed by 3-month androgen deprivation (leuprolide and chlormadinone acetate) and subsequent adjuvant endocrine therapy (leuprolide alone). The effects of preoperative androgen deprivation on survival, clinical relapse (serum prostate specific antigen, PSA, above the normal level, local recurrence, or distant metastases), and PSA relapse (PSA above the detectable level) were evaluated at 5 years or later after treatment. RESULTS: There were no significant differences in overall, cause-specific, clinical relapse-free, or PSA relapse-free survival rates between the two groups. In a subanalysis, no prostate cancer deaths or clinical relapses were noted in 29 patients with organ-confined disease (OCD: negativity of capsular invasion, seminal vesicle invasion, surgical margins or nodal involvement). The odds ratio for OCD depending on group assignment was 2.44 (95% confidence interval, CI 1.04-5.72), for group I, demonstrating a higher probability of having OCD. This ratio was increased to 4.00 (95% CI 1.06-15.16) if the analysis was conducted in a subpopulation with prostate specific antigen levels less than 35.6 ng/mL and with clinical stage B or C cancers. CONCLUSION: Preoperative androgen deprivation has no demonstrable benefit in 5-year outcomes for patients undergoing radical prostatectomy and adjuvant endocrine therapy. However, it did increase the probability of OCD, which was associated with no clinical relapse during the follow-up. A longer observation is needed to clarify the exact extent of the benefits in terms of survival.     

Prostate specific antigen and prostatic acid phosphatase for monitoring therapy of carcinoma of the prostate.

Serial serum prostatic acid phosphatase (PAP) and prostate specific antigen (PSA) measurements were performed in 871 patients treated with hormonal combination therapy for stage C (95 patients) or stage D2 (776) prostate cancer for an average followup of 26 months. The relative efficacy of serum PAP and PSA for predicting recurrence of the disease was evaluated by 2 statistical methods at the time of progression as well as 6 and 12 months before clinical relapse of disease using optimized cut-off values of 2.0 and 4.0 micrograms/l. for serum PAP and PSA, respectively. At the time of progression the sensitivity (plus or minus standard deviation) of the 2 tests was estimated at 61.1 +/- 3.2% and 86.7 +/- 3.1% for PAP and PSA, respectively, while the specificity (plus or minus standard deviation) was calculated at respective values of 79.6 +/- 1.3% and 92.4 +/- 4.1%. Receiver operating characteristic analysis disclosed a greater accuracy for PSA at 89.2 +/- 1.7% versus 78.7 +/- 1.6% (plus or minus standard deviation) for PAP. The somewhat lower positive predictive value of the PSA test (81.4% versus 89.6%) is more than compensated by its superior negative predictive value (92.4% versus 79.6%). The present data also show that serum PSA measurements are superior to those of serum PAP for predicting disease recurrence in stages C and D prostate cancer patients treated by combination endocrine therapy and they indicate that measurement of serum PAP does not add significantly to single measurement of serum PSA alone.     

Prognostic significance of changes in prostate-specific antigen in patients with metastasis prostate cancer after endocrine treatment

Patients with metastatic prostate cancer respond to androgen withdrawal therapy, but progression to androgen independence is frequently observed. To clarify the predictor of response to endocrine therapy, the role of PSA changes and the prognosis of the patients were evaluated in 115 Japanese cases of prostate cancer with distant metastases treated with androgen withdrawal therapy. When patients were divided according to the pretreatment PSA value (high, ≥500, median; 500 > PSA ≥ 100, low; 100>), patients whose initial PSA levels were high had a worse cause-specific survival. PSA value at 3 or 6 months following endocrine treatment, PSA nadir, and percent decrease of PSA were associated with prolonged survival. Clinical relapse was observed in 68 patients. Patients with distant recurrence had shorter time to PSA elevation than those with local recurrence. In metastatic prostate cancer patients treated with androgen withdrawal, serial measurement of PSA could distinguish nonfavorable responders early in the course of treatment and assist in monitoring for disease progression. This revised version was published online in June 2006 with corrections to the Cover Date.     

Changes in chromogranin a serum levels during endocrine therapy in metastatic prostate cancer patients

INTRODUCTION: The concept of neuroendocrine (NE) differentiation in prostate cancer has become more widely recognized as its diagnostic, prognostic, and therapeutic usefulness. PATIENTS AND METHODS: We enrolled 38 patients with stage D prostate cancer who underwent endocrine therapy by medical or surgical castration and oral antiandrogen. According to PSA response, serum levels of CGA as a marker of NE differentiation were measured at the multiple points of time; (1) pre-treatment, (2) complete response (CR), (3) a nadir level of PSA, (4) PSA failure or hormone independent progression. We compared these serum values in relation to efficacy of endocrine therapy. RESULTS: There was no correlation between serum PSA and CGA values. Patients consisted of 27 with CR and 11 without CR. Serum CGA increased as intervals of endocrine therapy became longer with positive correlation (p < 0.05). Its velocity was higher in patients with PSA failure than in those without it (6.98 vs. 2.09 ng/ml/month, p = 0.011). CONCLUSION: During endocrine therapy in metastatic prostate cancer patients, serum CGA values were not related to serum PSA levels, and increased as treatment periods became longer. It is suggested that CGA velocity has potential to predict androgen independent progression after endocrine therapy.     

Change in the ratio of free-to-total prostate-specific antigen during progression of advanced prostate cancer.

BACKGROUND: The ratio of free-to-total prostate-specific antigen (PSA) is different in benign prostatic hyperplasia and in the early stage of prostate cancer. The present study was undertaken to examine the ratio of free-to-total PSA in the advanced stage of this cancer and its subsequent change during course of the disease. METHODS: Free and total PSA were measured in sera collected from the following patients with benign and cancerous prostatic diseases: 47 cases of benign prostatic hypertrophy, nine in TIC with less than 10 ng/mL of total PSA, 11 in stage C, 16 in D2, 22 in remission under endocrine therapy, and 12 in relapse. In addition, PSA was measured sequentially in four other patients who were also in relapse. RESULTS: The ratio of free-to-total PSA was similar in early and advanced stages of untreated prostate cancer and was lower than that in benign prostatic hyperplasia. The ratio increased to the level of benign prostatic hyperplasia during remission from stages C and D2 under endocrine therapy. There was no correlation with the intervals from the start of the therapy to examination. Following relapse, the ratio came down gradually to the level obtained in untreated prostate cancer. CONCLUSION: The ratio of free-to-total PSA was similar in all stages of untreated prostate cancer. Response and relapse to endocrine therapy were associated with increase and decrease in ratio, respectively.     

Prostate specific antigen in the management of patients with localized adenocarcinoma of the prostate treated with primary radiation therapy.

The records of 143 patients treated at 5 institutions with external beam megavoltage irradiation for localized prostatic cancer were reviewed to evaluate post-treatment changes in prostate specific antigen (PSA) in the context of subsequent events. Complete responders were defined as patients clinically well with normal PSA, clinical failures were patients with documented local tumor recurrence or distant metastases and chemical failures were patients clinically well but with a PSA level above the upper limits of normal. Correlations with pre-treatment PSA values were also made for the 50 of 143 patients for whom pre-treatment PSA data were available. Median patient followup was 27 months (range 18 to 91 months). The data were analyzed with parametric and nonparametric univariate and multivariate statistical procedures. Pre-treatment PSA levels increased with increasing tumor stage (p = 0.004) but not with increasing summed Gleason pattern scores (p = 0.15). The probability of remaining a complete responder decreased with increasing stage (p = 0.008) but not with increasing Gleason score (p = 0.14). Increasing pre-treatment PSA correlated with clinical failure (p = 0.01) and chemical failure (p = 0.006). Of the patients with a pre-treatment PSA level of less than 4 times the upper limits of normal 83% remained as complete responders compared to 30% of those with a higher pre-treatment PSA (p = 0.0002). The return of PSA levels to the normal range within 6 months after treatment was strongly correlated with a favorable outcome when analyzed by multivariate logistic regression. The status at last followup of patients who had a normal PSA level at 6 months versus those with an elevated PSA level 6 months after treatment is 94% versus 8% for complete responders (p = 0.0001), 0% versus 60% for clinical failures (p = 0.002) and 6% versus 32% for chemical failures (p = 0.14). Similar results occurred when analyzing outcomes in relationship to PSA normalization within 12 months after treatment (p = 0.001 for clinical failures, p = 0.02 for chemical failures and p = 0.001 for complete responders). We conclude that the pre-treatment level of PSA is an independent prognostic factor for prostate cancer patients treated with primary radiation therapy, and that the failure of PSA to return to the normal range within 1 year after completion of treatment identifies a group of patients at high risk for tumor recurrence.     

Azacitidine favorably modulates PSA kinetics correlating with plasma DNA LINE-1 hypomethylation in men with chemonaïve castration-resistant prostate cancer

Background

Azacitidine is a hypomethylating agent that activates genes repressed by promoter methylation. Preclinically, demethylating agents reverse resistance of prostate cancer to androgen ablation. A phase II trial evaluated azacitidine for men with castration-resistant prostate cancer (CRPC) progressing on combined androgen blockade (CAB).

Methods

Chemonaïve patients with CRPC on CAB and PSA-doubling time (DT) < 3 months were eligible. The primary endpoint was prolongation of PSA-DT to ≥3 months. Correlation of biologic activity (fetal hemoglobin, plasma DNA LINE-1 methylation) with prolongation of PSA-DT was tested. CAB was continued and azacitidine 75 mg/m² was administered subcutaneously on days 1–5 of each 28-day cycle up to 12 cycles or until clinical progression/intolerable toxicities.

Results

Thirty-six patients were enrolled, 80.6% had metastatic disease, and 34 were evaluable. A PSA-DT ≥ 3 months was attained in 19 patients (55.8%). Overall median PSA-DT was significantly prolonged compared to baseline (2.8 vs. 1.5 months, P < 0.01). Fourteen patients had some PSA decline during therapy and 1 patient had a ≥30% decline compared with baseline. The median clinical progression-free survival was 12.4 weeks. Grade 3 toxicities included fatigue (12%), and neutropenia (6%), with 4 patients discontinuing due to toxicities. A trend in decreasing plasma DNA LINE-1 methylation was seen with longer treatment duration (P = 0.06), which significantly correlated with prolongation of PSA-DT (P = 0.02).

Conclusions

Azacitidine favorably modulates PSA kinetics in chemonaïve CRPC that correlates with decreasing plasma DNA LINE-1 methylation. Given the excellent tolerability, further development of azacitidine for CRPC may be warranted, with exploration of combination regimens.     

A phase II trial of imatinib mesylate in patients with biochemical relapse of prostate cancer after definitive local therapy

OBJECTIVE: To determine the biological effects of imatinib mesylate (STI-571, Gleevec; Novartis Pharmaceuticals, Inc., East Hanover, NJ, USA), as measured by prostate-specific antigen (PSA) kinetics in men with biochemical relapse of prostate cancer after definitive local therapy. PATIENTS AND METHODS: Men with prostate cancer, who had had definitive local therapy, with nonmetastatic recurrent disease as manifested by a rising PSA level, were enrolled on this phase II trial. Men received 400 mg of imatinib mesylate orally twice daily and continuously until disease progression or unacceptable toxicity. The PSA level was measured monthly. RESULTS: In all, 20 men with biochemically relapsed prostate cancer were treated. The median pretreatment PSA level was 5.4 ng/mL. Of the 19 evaluable men, one achieved a >or= 50% reduction in PSA level and two had decreases of <50%. For the 16 men in whom the on-treatment PSA doubling time (PSADT) could be calculated (those with increasing PSA level) the median PSADT did not increase significantly (5.8 vs 7.2 months, P = 0.64). Eleven of 20 men discontinued therapy due to toxicity and the trial was stopped early due to toxicity. CONCLUSIONS: Based on the lack of PSA modulation and pronounced toxicities leading to early closure of this trial, further study of single-agent imatinib mesylate at this dose (400 mg twice daily) cannot be recommended in this patient population.