S. Larry Goldenberg

Effects of intermittent androgen suppression on androgen‐dependent tumors. Apoptosis and serum prostate‐specific antigen

Background. Since postcastration progression of tumors to an androgen‐independent state appears to be linked to the cessation of androgen‐induced differentiation of tumorigenic stem cells, the authors hypothesized that the replacement of androgens at the end of a period of apoptotic regression might result in the regeneration of differentiated tumor cells with further apoptotic potential.

Intermittent androgen suppression in the treatment of prostate cancer: A preliminary report

OBJECTIVES To test the feasibility of using intermittent androgen suppression in the treatment of prostate cancer by taking advantage of the reversible action of medical castration. METHODS Observations were made on a group of 47 patients (clinical Stage D2, 14; D1, 10; C, 19; B2, 2; and A2, 2) with a mean follow-up time of 125 weeks. Treatment was initiated with combined androgen blockade and continued for at least 6 months until a serum prostate-specific antigen (PSA) nadir was observed. Medication was then withheld until the serum PSA increased to a mean value between 10 and 20 ng/mL. This cycle of treatment and no treatment was repeated until the regulation of serum PSA became androgen independent. RESULTS The first two treatment cycles lasted 73 and 75 weeks, with a mean time off therapy of 30 and 33 weeks and an overall mean percentage time off therapy of 41% and 45%, respectively. The mean time to achieve a nadir level of serum PSA was 20 weeks in cycle 1 and 18 weeks in cycle 2. Serum testosterone returned to the normal range within 8 weeks (range, 1 to 26) of stopping treatment. The off-treatment period in both cycles was associated with an improvement in sense of well-being and the recovery of libido and potency in the men who reported normal or near-normal sexual function before the start of therapy. In 7 patients with Stage D2 disease, the cancer progressed to an androgen-independent state. The mean and median times to progression were 128 weeks and 108 weeks, respectively. Seven patients have died, 1 from a noncancer-related illness, with mean and median overall survival times of 210 weeks and 166 weeks, respectively. CONCLUSIONS Prostate cancer is amenable to control by intermittent androgen suppression. This approach affords an improved quality of life when the patient is off therapy. It also results in reduced toxicity and cost of treatment and possibly delays tumor progression. Whether survival is affected in a beneficial or adverse way remains to be studied in a randomized, prospective study.

Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO guideline

PURPOSE The purpose of this guideline is to provide a clinical framework for the use of radiotherapy after radical prostatectomy as adjuvant or salvage therapy. MATERIALS AND METHODS A systematic literature review using the PubMed®, Embase, and Cochrane databases was conducted to identify peer-reviewed publications relevant to the use of radiotherapy after prostatectomy. The review yielded 294 articles; these publications were used to create the evidence-based guideline statements. Additional guidance is provided as Clinical Principles when insufficient evidence existed. RESULTS Guideline statements are provided for patient counseling, the use of radiotherapy in the adjuvant and salvage contexts, defining biochemical recurrence, and conducting a re-staging evaluation. CONCLUSIONS Physicians should offer adjuvant radiotherapy to patients with adverse pathologic findings at prostatectomy (i.e., seminal vesicle invasion, positive surgical margins, extraprostatic extension) and should offer salvage radiotherapy to patients with prostatic specific antigen or local recurrence after prostatectomy in whom there is no evidence of distant metastatic disease. The offer of radiotherapy should be made in the context of a thoughtful discussion of possible short- and long-term side effects of radiotherapy as well as the potential benefits of preventing recurrence. The decision to administer radiotherapy should be made by the patient and the multi-disciplinary treatment team with full consideration of the patients history, values, preferences, quality of life, and functional status. Please visit the ASTRO and AUA websites (http://www.redjournal.org/webfiles/images/journals/rob/RAP%20Guideline.pdf and http://www.auanet.org/education/guidelines/radiation-after-prostatectomy.cfm) to view this guideline in its entirety, including the full literature review.

Combined diffusion‐weighted and dynamic contrast‐enhanced MRI for prostate cancer diagnosis—Correlation with biopsy and histopathology

To determine whether the combination of diffusion‐weighted (DW) and dynamic contrast‐enhanced (DCE) MRI provides higher diagnostic sensitivity for prostate cancer than each technique alone.

Assessing information and decision preferences of men with prostate cancer and their partners

The purpose of this study was to identify and compare information and decision preferences of men with prostate cancer and their partners at the time of diagnosis. A convenience sample of 80 couples was recruited from The Prostate Centre in Vancouver, Canada. Participants used a computerized version of two previously used measures with this population: Control Preferences Scale and Information Survey Questionnaire. Results showed that men had a preference to play either an active or a collaborative role in decision making with their physician (92.5%) and partners (100%). The majority (55%) of partners wanted to play a collaborative role in treatment decision making. Couples identified prognosis, stage of disease, treatment options, and side effects as the top 4 information preferences. Men ranked information on sexuality more important than partners, and partners ranked information on home self-care higher than men. Men who had sons, a positive family history, and lower levels of education ranked heredity risk significantly higher. Profiles of information categories did not differ according to role preferences of either men or partners. The computer program has been shown to be a reliable and acceptable method of assessing information and decision preferences of these couples. An individualized approach is suggested, given the high reliability of individual’s profiles.

Intermittent androgen suppression delays progression to androgen-independent regulation of prostate-specific antigen gene in the LNCaP prostate tumour model

In most patients with prostate cancer, continuous androgen suppression (CAS) therapy causes tumour regression and an accompanying decrease in serum prostate specific antigen (PSA). However, with tumour progression, regulation of both tumour growth and PSA gene expression becomes androgen-independent. Because androgen resistance develops, in part, from adaptive cell survival mechanisms activated by androgen withdrawal, we hypothesize that intermittent re-exposure to androgens may prolong time to androgen-independent progression. The objective of this study was to determine whether intermittent androgen suppression (IAS) could delay the onset of androgen-independent PSA gene regulation in LNCaP prostate tumour model when compared to CAS. Five or six cycles of IAS were possible before progression developed. IAS prolonged time to androgen-independent PSA gene regulation from an average of 26 days in CAS to 77 days in IAS. Serum PSA increased above pre-castrate levels in all mice treated with CAS by 28 days post-castration, but remained below pre-castrate levels in 75% of IAS-treated mice by 60 days post-castration. By 15 weeks post-castration, serum PSA levels increased 7-fold above pre-castrate levels in CAS-treated mice compared to 1.9-fold increase in IAS-treated mice. PSA mRNA expression levels highly correlated with serum PSA levels in both groups. Maintenance of androgen dependency through IAS may be due to androgen-induced differentiation and/or down-regulation of androgen-suppressed gene expression.

RANDOMIZED, PROSPECTIVE, CONTROLLED STUDY COMPARING RADICAL PROSTATECTOMY ALONE AND NEOADJUVANT ANDROGEN WITHDRAWAL IN THE TREATMENT OF LOCALIZED PROSTATE CANCER

PURPOSE A prospective, multicenter, randomized study was done to test the hypothesis that neoadjuvant androgen withdrawal decreases the incidence of positive margins following radical prostatectomy for localized prostate cancer. MATERIALS AND METHODS Observations were made of 213 patients randomized to undergo radical prostatectomy alone (101) or to receive a 12-week course of 300 mg. cyproterone acetate daily followed by surgery (112). Groups were similar at baseline in terms of clinical stage, serum prostate specific antigen and Gleason score. Of 192 patients available for efficacy analysis 9 had stage T1b, 8 stage T1c, 63 stage T2a, 36 stage T2b and 76 stage T2c disease. RESULTS One or more positive surgical margins were found in 59 of 91 patients (64.8%) in the surgery only group compared to 28 of 101 (27.7%) in the cyproterone acetate group (p = 0.001). Patients who received preoperative therapy had a statistically significantly lower rate of apical margin involvement than those who did not (17.8 versus 47.8%, respectively, p < 0.0001). There was no statistically significant difference in surgical (p = 0.8645) or postoperative (p = 0.173) complications between the 2 groups. CONCLUSIONS Neoadjuvant androgen withdrawal with a 12-week course of 300 mg. cyproterone acetate daily results in a lower rate of positive margins without adversely affecting postoperative recovery. The impact on patient survival will be determined by long-term followup.

Provision of individualized information to men and their partners to facilitate treatment decision making in prostate cancer.

PURPOSE/OBJECTIVES To determine if providing individualized information to men who are newly diagnosed with prostate cancer and their partners would lower their levels of psychological distress and enable them to become more active participants in treatment decision making. DESIGN Quasiexperimental, one group, pretest/post-test. SETTING The Prostate Centre at Vancouver General Hospital in British Columbia, Canada. SAMPLE Convenience sample of 74 couples. 73 men had early-stage prostate cancer. Mean age of the men was 62.2 years, and mean age of the partners was 58.1 years. The majority (> 50%) had received their high school diplomas. METHODS Respondents completed measures of decision preferences and psychological distress at the time of diagnosis and four months later. All participants used a computer to identify their information and decision preferences. Computer-generated, graphic printouts were used to guide the information counseling session. FINDINGS Patients reported assuming a more active role in medical decision making than originally intended, partners assumed a more passive role in decision making than originally intended, and all participants had lower levels of psychological distress at four months. CONCLUSIONS Evidence supports the need to provide informational support to couples at the prostate cancer diagnosis to facilitate treatment decision making and lower levels of psychological distress. Future research is needed to evaluate this type of approach in the context of a randomized clinical trial design. IMPLICATIONS FOR NURSING The personalized, computer-graphic printouts can provide clinicians with an innovative method of guiding information counseling and providing decisional support to men with prostate cancer and their partners.

Adjuvant and salvage radiation therapy after prostatectomy: American society for radiation oncology/american urological association guidelines

PURPOSE The purpose of this guideline was to provide a clinical framework for the use of radiation therapy after radical prostatectomy as adjuvant or salvage therapy. METHODS AND MATERIALS A systematic literature review using PubMed, Embase, and Cochrane database was conducted to identify peer-reviewed publications relevant to the use of radiation therapy after prostatectomy. The review yielded 294 articles; these publications were used to create the evidence-based guideline statements. Additional guidance is provided as Clinical Principles when insufficient evidence existed. RESULTS Guideline statements are provided for patient counseling, use of radiation therapy in the adjuvant and salvage contexts, defining biochemical recurrence, and conducting a restaging evaluation. CONCLUSIONS Physicians should offer adjuvant radiation therapy to patients with adverse pathologic findings at prostatectomy (ie, seminal vesicle invastion, positive surgical margins, extraprostatic extension) and salvage radiation therapy to patients with prostate-specific antigen (PSA) or local recurrence after prostatectomy in whom there is no evidence of distant metastatic disease. The offer of radiation therapy should be made in the context of a thoughtful discussion of possible short- and long-term side effects of radiation therapy as well as the potential benefits of preventing recurrence. The decision to administer radiation therapy should be made by the patient and the multidisciplinary treatment team with full consideration of the patients history, values, preferences, quality of life, and functional status. The American Society for Radiation Oncology and American Urological Association websites show this guideline in its entirety, including the full literature review.

Bacterial sepsis after prostate biopsy--a new perspective.

OBJECTIVES To determine the incidence of sepsis following transrectal ultrasound (TRUS)-guided prostate biopsy at our center. METHODS We retrospectively reviewed a group of 24 men who presented with urosepsis after undergoing TRUS biopsy at our center. RESULTS Of the 24 men, 22 were given prophylactic ciprofloxacin. The median time to presentation of sepsis was 1 day after biopsy. The median length of hospitalization was 4 days. Escherichia coli was the most frequent cause of urosepsis (67%). Variable resistance patterns were observed. Enterobacter cloacae and Streptococcus viridans were isolated in 2 cases. No bacteria were isolated in 6 cases. Two patients who received extensive antibiotic prophylaxis still developed urosepsis. Treatment of patients infected with multiresistant anaerobic strains using metronidazole among others, proved successful. High sensitivities toward cefazolin, gentamicin, and tobramycin were observed. The number of cases reported was likely an underestimation, because some patients may have reported to other hospitals and were not captured by this study. In addition, some patients may not have developed infection and urosepsis despite harboring ciprofloxacin-resistant bacteria. CONCLUSIONS Prophylactic ciprofloxacin is still a useful option for the prevention of urosepsis after TRUS biopsy, as the incidence is relatively low. For the patient who develops urosepsis after TRUS biopsy, ciprofloxacin resistance needs to be suspected and the treatment regime should be tailored to the resistance profiles of the local region, the patients medical history, and the culture and sensitivity reports.