Biochemical Relapse Of Prostate Cancer Research Articles

Dosimetric Comparison of Three-Dimensional Conformal Radiotherapy in Salvage Radiotherapy for PSA Relapse after Radical Prostatectomy

The purpose of this study is to compare three-dimensional conformal radiotherapy (3D-CRT) plans in a setting of salvage radiotherapy after radical prostatectomy (RP) and to simulate whether dose escalation is possible with the most adequate 3D-CRT technique. This study included consecutive 10 patients underwent salvage radiotherapy (RT) for biochemical relapse of prostate cancer after RP. Normal structures included the rectum, bladder, and femoral head. For each patient, four different treatment plans including four fields RT (4F-RT), dynamic conformal arc radiotherapy (DCAT), six fields RT (6F-RT), and DCAT with rectum hollow-out technique (DCAT-HO), were created to entire the prostate bed. The parameters of the maximum and mean doses received by organs at risk (OAR), target coverage, dose homogeneity for the planning target volume (PTV) were compared. All plans were considered to be clinically tolerable for PTV coverage and dose homogeneity. The rectum sparing at the high dose area for DCAT-HO was considered to be the most superior to those for other three techniques by comparison of the dose delivered to a 1%, 5%, and 10% volume of the rectum. In the simulation of dose escalation to 70 Gy with DCAT-HO, OAR met a requirement of the dose-volume constraints. However, in the simulation of dose escalation to 72 Gy, the rectum that receives 60 to 65 Gy and bladder that receives 65 Gy exceeded the optimal dose-volume constraints. DCAT-HO was considered to be one of the most appropriate techniques in 3D-CRT if dose escalation to 70 Gy might be needed in a setting of salvage RT after RP in the future.

POD-11.04: PSA Nadir After Radical Prostatectomy Measured by Ultrasensitive Assay Predicts the Risk of Biochemical Relapse of Prostate Cancer

After successful radical prostatectomy prostate specific antigen (PSA) should become undetectable by conventional PSA assays. However, ultrasensitive PSA assay techniques allow considerably lower limit of detection than standard PSA assays. The objective of this study was to investigate weather the dynamic of postoperative ultrasensitive PSA decrease could predict the biochemical relapse of prostate cancer.

Combined low‐dose flutamide plus finasteride vs low‐dose flutamide monotherapy for recurrent prostate cancer: a comparative analysis of two phase II trials with a long‐term follow‐up

To compare the efficacy and tolerability of peripheral androgen blockade using combined low-dose flutamide plus finasteride vs low-dose flutamide monotherapy for treating biochemical relapse after the definitive management of prostate adenocarcinoma. Fifty-six men treated for biochemical relapse of prostate cancer were enrolled prospectively in a phase II trial at the Walter Reed Army Medical Center from 1997 to 2001. Thirty-six men were treated with flutamide (125 mg twice daily) and finasteride (5 mg twice daily), and 20 men received low-dose flutamide only after biochemical recurrence (prostate-specific antigen, PSA, level > or =0.4 ng/mL). Cox proportional hazards analyses were used to compare the risk of progression between the groups. Patients on combined and monotherapy had a median follow-up of 54 and 43.5 months, respectively. Seven men (19%) in the combined arm remain in the study with no progression, while five (25%) on monotherapy continue and are progression-free. Men on combined therapy had a greater decrease in their PSA level (P = 0.002). Multivariate analysis showed that men on combined therapy had significantly less risk of progression than men on monotherapy (hazard ratio 0.21, 95% confidence interval 0.07-0.63, P = 0.005). There was no significant difference in the frequency of side-effects between the groups. Toxicities were reported to be mild. Our analysis suggests the therapeutic value of low-dose flutamide alone or combined with finasteride as first-line agents in a possible graduated approach for treating PSA-only recurrent prostate cancer. Due to unwanted metabolic effects associated with traditional hormonal agents, phase III trials comparing both regimens with current therapies are warranted.

Early salvage radiotherapy for patients with PSA relapse after radical prostatectomy

To assess the effectiveness of early salvage radiotherapy (RT) for patients with prostate-specific antigen (PSA) relapse after radical prostatectomy (RP) retrospectively. Fifty-one patients underwent salvage RT for biochemical relapse of prostate cancer initially treated with RP. All patients had persistent or rising PSA >0.20 ng/ml at some point after surgery, or three successive PSA elevations after a postoperative nadir if PSA was < or =0.20 ng/ml. Most (96%) of pre-RT PSA were less or equal to 0.50 ng/ml, and median value was 0.25 ng/ml (range, 0.05-0.90 ng/ml). Median RT dose was 60 Gy (range, 50-66 Gy). Multivariate Cox regression analysis was performed for PSA before RP and salvage RT, margin status, seminal vesicle involvement, extracapsular invasion, Gleason score, PSA doubling time (PSADT), and RT dose to identify significant predictors of biochemical outcome. Median follow-up was 36 months. The 3-year biochemical no evidence of disease rate (bNED) was 55.1%. On multivariate analysis only the following factors were significantly associated with improved bNED: PSADT >3.0 months (P = 0.008), Gleason score < or =7 (P = 0.01), and RT dose > or =60 Gy (P = 0.028). Although a total dose of 60 Gy was effective at a low pre-RT PSA levels with short follow-up, an RT dose > or =60 Gy resulted in superior biochemical outcomes even in patients with a pre-RT PSA < or =0.50 ng/ml.

A randomized double blind phase I-II study to determine the tolerability/efficacy of two different doses of lenalidomide (L), CC- 5013, in biochemically relapsed (BR) prostate cancer (PC) patients (pts) (M0) after local treatment (LT)

5130 Background: BR following LT is common in PC with no defined standard treatment. Lenalidomide (L) is an immunomodulatory agent with anti-angiogenic and direct antitumor effects. Methods: This trial was designed to evaluate a dose-effect relationship of L in BR PC. Pts were randomized to either 5 or 25 mg/day(d), PO, d 1–21 (28-d cycles); then stratified by PSADT (&lt; 3, 3–8.9, ≥ 9 mos), LT and prior ADT. Eligible pts had: rising PSA (≥1 ng/mL), M0 disease, testosterone &gt; 150 ng/mL, adequate bone marrow, renal, and hepatic function. Baseline and Q 2 mos PSA's were processed after Q 6 mos of L, along with CT and bone scan. Toxicity exams were Q mo. Primary endpoints are safety and progression after 6 mo of L (defined by a confirmed ↑ in PSA &gt; 25% over the baseline value or mets). Secondary endpoints are changes of slopes in PSA related to pharmacokinetics (pk). A sample size of 30 pts/arm provides an 85% power to detect a PSA progression rate of 40% (compared to 80% predicted ) with a Type I error = 0.05 (Fishers exact test). Results: 59 pts were entered July 20, 2006-December 31, 2008. Pooled data from the 2 arms: median: age 64 (50–81), ECOG PS 0, baseline PSA 9.3 ng/ml (1.3–92.8 ng/ml). 16 pts had PSADT &lt;3 mos, 26 from 3–8.9 mos, and 17 ≥ 9 mos. Median: F/U on all 59 pts is 351 + d (9 +-887+d); # cycles = 6 (1–30). Thus far, 44/59 pts completed 6 cycles of L (1 had PD, 6 stopped L due to toxicity, 8 too early). 22 /44 who completed 6 mos of L remained on L &gt; 6 mos ( 7+-30+ mos); including 7 pts ≥ 24 mos. Of 44 pts, blinded evaluation of PSA's at 6 mos: 4 pts had ≥ 50% ↓, 22 had stable PSA,17 had PD, 1 too early . Rash was DLT. Other Gr toxicities: appendicitis, abd pain, neck pain, venous thrombolic disease, fatigue, pruritus. Conclusions: Preliminary data prior to unblinding the study treatment arms, from pooled data, suggest that L may be administered &gt; 6 mos with acceptable toxicity, and is associated with PSA declines and long term stabilization in pts with BR. Supported by a grant from Celgene Corporation. Data coordination infrastructure is supported by the Prostate Cancer Foundation and The James Stine research fund. [Table: see text]

Novel multi‐peptide vaccination in Hla‐A2+ hormone sensitive patients with biochemical relapse of prostate cancer

A phase I/II trial was conducted to assess feasibility and tolerability of tumor associated antigen peptide vaccination in hormone sensitive prostate carcinoma (PC) patients with biochemical recurrence after primary surgical treatment. Nineteen HLA-A2 positive patients with rising PSA without detectable metastatic disease or local recurrence received 11 HLA-A*0201-restricted and two HLA class II synthetic peptides derived from PC tumor antigens subcutaneously for 18 months or until PSA progression. The vaccine was emulgated in montanide ISA51 and combined with imiquimod, GM-CSF, mucin-1-mRNA/protamine complex, local hyperthermia or no adjuvant. PSA was assessed, geometric mean doubling times (DT) calculated and clinical performance monitored. PSA DT of 4 out of 19 patients (21%) increased from 4.9 to 25.8 months during vaccination. Out of these, two patients (11%) exhibited PSA stability for 28 and 31 months which were still continuing at data cut-off. One patient showed no change of PSA DT during vaccination but decline after the therapy. Three patients had an interim PSA decline or DT increase followed by DT decrease compared to baseline PSA DT. Three of the responding patients received imiquimod and one the mucin-1-mRNA/protamine complex as adjuvant; both are Toll-like receptor-7 agonists. Eleven (58%) patients had progressive PSA values. The vaccine was well tolerated, and no grade III or IV toxicity occurred. Multi-peptide vaccination stabilized or slowed down PSA progress in four of 19 cases. The vaccination approach is promising with moderate adverse events. Long-term stability delayed androgen deprivation up to 31 months. TLR-7 co-activation seems to be beneficial.

Lycopene for Advanced Hormone Refractory Prostate Cancer: A Prospective, Open Phase II Pilot Study

We investigated the influence of lycopene on the clinical and laboratory course in men with hormone refractory prostate cancer. To our knowledge this study represents the first time that subjective assessments of the course of therapy have been recorded. We performed a prospective, open phase II pilot study, in which patients with progressive hormone refractory prostate cancer were included. Lycopene supplementation (15 mg) was given daily for 6 months. Followup laboratory tests and clinical examinations were done monthly. Changes to analgesic use and quality of life (European Organisation for Research and Treatment of Cancer QLQ-C30) were measured. The study end point was a significant change in serum prostate specific antigen, clinical progression or the end of the 6-month observation period. A total of 18 patients 64 to 85 years old (median age 73) were enrolled in the study during a 20-month period, of whom 17 could be analyzed. Five of the 17 patients (29%) withdrew from the study prematurely, including 4 of 5 because of prostate specific antigen progression and/or tumor associated complications, and 1 due to an allergic reaction to lycopene. Median prostate specific antigen doubled in 6 months from 42.7 ng/ml (range 13.8 to 521.6) in 17 patients to 96.4 ng/ml (range 13.5 to 1,240) in 12. Stable prostate specific antigen was observed in 5 of 17 patients (29%). None of the patients had a greater than 50% decrease in prostate specific antigen. Patients experienced a slight deterioration in mean health status at the end of the study compared to the outset. However, two-thirds of the patients experienced an improved or unchanged situation regardless of the clinical and biochemical course. No clinically relevant benefits were shown for patients with advanced stages of the disease.

Androgen-deprivation-therapy-induced fractures in men with nonmetastatic prostate cancer: what do we really know?

Androgen deprivation therapy (ADT) alone or in combination with radiation therapy or other drugs is increasingly used for the treatment of localized, high-risk, or biochemical relapse of prostate cancer (PC). Bone mineral density (BMD) loss is rapid during the first year of ADT; up to 4.6% of total hip, femoral neck, and lumbar spine BMD loss has been reported in PC patients without bone metastases (nonmetastatic PC). In prospective studies, concurrent administration of a bisphosphonate or selective estrogen receptor modulator stabilized or increased BMD. Results of retrospective studies of ADT-treated patients who did not receive antiresorptive therapy have demonstrated a 21-37% increase in fracture risk. Because of the documented bone loss and increased fracture risk, patients should receive adequate counseling, monitoring, and therapy aimed at preventing or treating ADT-induced bone loss. Future studies should address the long-term impact of antiresorptive therapy on actual fracture rate and the impact on quality of life and healthcare costs.

Duration of the first off treatment period is associated with time to androgen independence (AI) and survival in men with localized or biochemical relapse of prostate cancer treated on a prospective trial of intermittent androgen deprivation (IAD)

5146 Background: Patients (pts) with localized prostate cancer or biochemical relapse who are treated with AD eventually develop AI and die. In an effort to better understand the natural history of this population, various characteristics of the patients and the first cycle of IAD were analyzed. Methods: Eligible pts had histological diagnosis of prostate cancer, no evidence of bone metastases by bone scan or visceral disease by CT scan, and at least 2 consecutive rising PSA = 2 weeks apart after diagnosis, radical prostatectomy (RP), or radiation therapy (XRT). Pts were treated with IAD consisting of 9 months of leuprolide acetate and an anti-androgen. Subsequently AD was stopped and monthly PSA and testosterone levels were followed during the off treatment period (Toff) until the PSA reached a threshold value (1 ng/mL if prostate removed or 4 ng/mL if prostate intact). At that time AD was resumed as before in a new cycle. Pts were treated until AI, defined as two rising PSAs while on AD with a castrate level of testosterone. Results: To date, 57 of 88 accrued pts are evaluable for this analysis. The median age at diagnosis is 62.2 yrs (range 43.9–77.4 yrs), median Gleason sum is 7. For the 49 pts with biochemical relapse after prior RP or XRT, median time from diagnosis to PSA relapse is 3.2 yrs (0–14.7 yrs) and from diagnosis to IAD was 4.9 yrs (range 0.1–14.9 yrs). For the 8 pts with no prior therapy, median time from diagnosis to IAD is 0.2 yrs (range 0–3.9 yrs). The median PSA value for all pts at study entry is 16 ng/mL (range 4–175 ng/mL); the value at study entry or after 3, 5, or 7 months of AD is not associated with time to AI or survival. Entry PSA is predictive of length of first Toff, and the length of the first Toff is associated with both time to AI (P&lt;0.010) and survival (P&lt;0.01). Conclusions: The duration of the first Toff in other studies of IAD should be evaluated for similar associations with time to AI and survival. No significant financial relationships to disclose.

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

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. 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. 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. 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.

Phase I-II prospective dose-escalating trial of lycopene in patients with biochemical relapse of prostate cancer after definitive local therapy

Objectives To report a prospective trial of lycopene supplementation in biochemically relapsed prostate cancer. Methods A total of 36 men with biochemically relapsed prostate cancer were enrolled in a dose-escalating, Phase I-II trial of lycopene supplementation. Six consecutive cohorts of 6 patients each received daily supplementation with 15, 30, 45, 60, 90, and 120 mg/day for 1 year. The serum levels of prostate-specific antigen (PSA) and plasma levels of lycopene were measured at baseline and every 3 months. The primary endpoints were PSA response (defined as a 50% decrease in serum PSA from baseline), pharmacokinetics, and the toxicity/tolerability of this regimen. Results A total of 36 patients were enrolled. The median age was 74 years (range 56 to 83), with a median serum PSA at entry of 4.4 ng/mL (range 0.8 to 24.9). No serum PSA responses were observed, and 37% of patients had PSA progression. The median time to progression was not reached. Toxicity was mild, with 1 patient discontinuing therapy because of diarrhea. Significant elevations of plasma lycopene were noted at 3 months and then appeared to plateau for all six dose levels. The plasma levels for doses between 15 and 90 mg/day were similar, with additional elevation only at 120 mg/day. Conclusions Lycopene supplementation in men with biochemically relapsed prostate cancer is safe and well tolerated. The plasma levels of lycopene were similar for a wide dose range (15 to 90 mg/day) and plateaued by 3 months. Lycopene supplementation at the doses used in this study did not result in any discernible response in serum PSA.

Activation of nuclear factor-κB in human prostate carcinogenesis and association to biochemical relapse

Nuclear factor (NF)-κB/p65 regulates the transcription of a wide variety of genes involved in cell survival, invasion and metastasis. We characterised by immunohistochemistry the expression of NF-κB/p65 protein in six histologically normal prostate, 13 high-grade prostatic intraepithelial neoplasia (PIN) and 86 prostate adenocarcinoma specimens. Nuclear localisation of p65 was used as a measure of NF-κB active state. Nuclear localisation of NF-κB was only seen in scattered basal cells in normal prostate glands. Prostatic intraepithelial neoplasias exhibited diffuse and strong cytoplasmic staining but no nuclear staining. In prostate adenocarcinomas, cytoplasmic NF-κB was detected in 57 (66.3%) specimens, and nuclear NF-κB (activated) in 47 (54.7%). Nuclear and cytoplasmic NF-κB staining was not correlated (P=0.19). By univariate analysis, nuclear localisation of NF-κB was associated with biochemical relapse (P=0.0009; log-rank test) while cytoplasmic expression did not. On multivariate analysis, serum preoperative prostate specific antigen (P=0.02), Gleason score (P=0.03) and nuclear NF-κB (P=0.002) were independent predictors of biochemical relapse. These results provide novel evidence for NF-κB/p65 nuclear translocation in the transition from PIN to prostate cancer. Our findings also indicate that nuclear localisation of NF-κB is an independent prognostic factor of biochemical relapse in prostate cancer.

1104 ORAL Clinical application of 11C-Choline PET in patients with biochemical relapse of prostate cancer

1104 ORAL Clinical application of 11C-Choline PET in patients with biochemical relapse of prostate cancer

Marimastat in the Treatment of Patients with Biochemically Relapsed Prostate Cancer: A Prospective Randomized, Double-Blind, Phase I/II Trial

To evaluate the safety and biological activity of three different doses of marimastat given for 6 months to patients with biochemically relapsed prostate cancer. Patients with a biochemical relapse within 2 years of primary therapy, a prostate-specific antigen (PSA) increase of at least 50% within 6 months of study entry, and no prior systemic therapy were eligible. Patients were randomized to receive marimastat at total daily doses of 5, 20, or 40 mg for 6 months unless dose-limiting toxicity or new evidence of disease occurred. Thirty-nine patients were treated. Grade 3-4 reversible musculoskeletal toxicity was the only dose-limiting toxicity. Increasing dose was associated with increased probability of experiencing dose-limiting toxicity (5.9%, 42.9% and 88.9% for the 5, 20, and 40 mg groups, respectively; P = 0.03). Accrual was discontinued early on the two higher dose levels due to toxicity. A significant decrease in PSA slope was shown in the 20 mg group when compared with the 5 mg group (0.117 and -0.0046, respectively; P = 0.03) The 40 mg group (versus the 5 mg group) showed a similar change (0.109) with a trend towards significance (P = 0.07). An increased serum matrix metalloproteinase 2 level at month 3 compared with the baseline correlated with a decrease in PSA slopes (Slope, 0.001; 95% confidence interval, 0.0002-0.0018; P = 0.02). These data suggest that marimastat has a biological effect and may effectively delay progression in patients with biochemical relapsed prostate cancer, as shown by the change in PSA slope; however, dose-limiting toxicity at active doses is significant. Confirmatory studies with less toxic matrix metalloproteinase inhibitors employing more conventional end points are indicated. This design is feasible and potentially efficient for screening antimetastatic agents.

Partners assessment of sexual function on androgen suppression (AS) for treatment of biochemical relapse of prostate cancer

8261 Background: AS leads to significant loss in quality of life domains of sexual and intimate relationships for the partner as well as for the patient. Men with biochemical relapse of prostate cancer live for years and therefore, defining the impact of AS on sexuality and intimacy issues of a couple is important for designing future intervention trials aimed at addressing these problems. Methods: Men with biochemical relapse of prostate cancer were entered on a clinical trial of IAS. The patient and his partner each answered questionnaires at baseline and after 9 months of AS. The partner was asked to answer the same questionnaire according to her own perceptions of the answers as they pertained to the patient. Results: 14 men were married, eugonadal, and Caucasian with a median age of 64.5 years (range 51.8 to 77.2). At baseline, 9 men and 11 women reported erectile dysfunction (ED); 9 couples had no sexual activity during the past month. After 9 months of AS, 13 men and 14 women reported ED; 13 couples had no sexual activity in the past month. Conclusions: Not surprisingly, AS adversely impacted sexual desire, overall sexual function and frequency of sexual activity in most patients. One couple maintained sexual activity throughout. However, baseline sexual function was already poor in the majority of patients. This emphasizes the need to assess baseline function and include the couple rather than just the patient in therapeutic strategies aimed at enhancing sexuality and intimacy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi, TAP

PSA doubling time (PSA-DT) during the “off treatment” interval in men with biochemical relapse of prostate cancer treated with intermittent androgen suppression (IAS)

4670 Background: PSA-DT has been shown to be a surrogate marker for mortality in patients who have biochemical relapse after either RP or XRT (D’Amico, J Urol 172 2004). These men are often treated...

PSA doubling time kinetics during prostate cancer biochemical relapse after external beam radiation therapy

To investigate whether prostate-specific antigen PSA doubling time (PSADT) is constant in men with biochemical prostate cancer relapse after external beam radiotherapy (EBRT). A total of 513 men treated radically with EBRT, with or without androgen ablation (AA), between 1993 and 2000, developed biochemical relapse. The slope of the ln (PSA) vs. time graph is calculated for the first two values after PSA nadir (first slope), the last two recorded PSAs (last slope), and all values excluding the first and final PSA (mid slope). Differences in these slopes were compared statistically with subgroup analysis for AA and secondary intervention. For men treated with EBRT and AA first slope was faster than either mid slope (p = 0.031) or last slope (p < 0.001). Men treated with EBRT alone had no change in PSADT over time unless they subsequently received secondary intervention. This group had a more rapid last slope compared with mid slope (p < 0.001). PSA initially rises more rapidly after AA cessation, probably because of testosterone recovery. A subgroup of patients, who received secondary intervention after treatment with radiotherapy alone, showed a change in PSADT, to a faster velocity. This greater than constant exponential PSA growth is presumably the catalyst for secondary intervention. Otherwise, PSADT did not change during prostate cancer biochemical relapse.

957 poster Salvage intensity-modulated radiotherapy (IMRT) for biochemical relapse of prostate cancer after radical prostatectomy: initial clinical results

957 poster Salvage intensity-modulated radiotherapy (IMRT) for biochemical relapse of prostate cancer after radical prostatectomy: initial clinical results