Lorne D. Sullivan

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.

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.

Postoperative Radiotherapy for Stage pT3 Carcinoma of the Prostate: Improved Local Control

PURPOSE We determined whether radiotherapy after radical prostatectomy leads to improved results in patients with stage pT3 carcinoma of the prostate. MATERIALS AND METHODS In a prospective nonrandomized study of 203 patients with clinical stage T2 prostate cancer treated with radical prostatectomy 88 underwent surgery alone, 89 received early postoperative radiotherapy generally because of pathological stage T3 disease and 26 received delayed radiotherapy for local recurrence. The disease was stage pT3N0/X in 135 patients. RESULTS For patients with pathological stage T3 cancer actuarial local recurrence rates were significantly decreased in the early postoperative radiotherapy group compared to the surgery only group (p = 0.005), while actuarial metastatic rates (p = 0.6) and cause specific survival rates (p = 0.04) were not significantly different. Multivariate analysis for all patients in both groups identified adverse features of increased postoperative prostate specific antigen levels, seminal vesicle involvement, lack of postoperative radiotherapy and positive lymph nodes. Late toxicity was severe (Radiation Therapy Oncology Group grade 3 or 4) in 13 surgery only and 17 early postoperative radiotherapy group patients. Of those who were potent postoperatively the incidence of impotence in the early postoperative radiotherapy group was 89% compared to 59% in the surgery only group (p = 0.003). For patients treated with delayed radiation for clinical local recurrence the actuarial local control rate was 54% after 10 years. CONCLUSIONS Local radiotherapy appears to improve local control of stage pT3 cancer but has no impact on overall survival.

The Correlation of Multichannel Urodynamic Pressure-Flow Studies and American Urological Association Symptom Index in the Evaluation of Benign Prostatic Hyperplasia

PURPOSE We correlated multichannel pressure-flow urodynamics and the American Urological Association (AUA) symptom index in the evaluation of benign prostatic hyperplasia. MATERIALS AND METHODS We evaluated 121 consecutive, symptomatic patients older than 55 years with the AUA symptom score and multichannel pressure-flow urodynamic studies. Testing was performed during a single session and the data obtained from 103 patients were plotted on the Schäfer nomogram for assessment of outflow obstruction. Linear regression statistical analysis was used to determine correlations. RESULTS There was no significant correlation between uroflowmetry and Schäfer curves (r = 0.173 to 0.326), uroflowmetry and AUA symptom scores (r = 0.134 to 0.153) and, most importantly, AUA symptom scores and Schäfer curves (r = 0.025 to 0.137). CONCLUSIONS We conclude that these modalities measure independent variables, and should not be linked in the evaluation and treatment decision of the patient with prostatism.

Long-term neoadjuvant hormone therapy prior to radical prostatectomy: evaluation of risk for biochemical recurrence at 5-year follow-up

OBJECTIVES To assess the effects of 8 months of neoadjuvant therapy on pathologic stage and biochemical recurrence rates. METHODS One hundred fifty-six men with clinically localized prostate cancer were treated with neoadjuvant combined androgen withdrawal therapy for 8 months prior to radical prostatectomy. Preoperative clinical stage, Gleason score, and serum prostate-specific antigen (PSA) levels were compared with treatment outcome (pathologic stage and PSA recurrence). RESULTS PSA at diagnosis was 10 microg/L or higher in 36% with a mean of 11.5 microg/L. Clinical stage was T1c in 18%, T2 in 74%, and T3a in 8%. Gleason score was 6 or lower in 76% and 7 or higher in 24%. Pathologic stage was T0 in 13%, T2 in 66%, T3 (specimen confined) in 13%, T3 (margin positive) in 6%, and TxN+ in 2%. Incidence of positive margins increased with clinical stage T3a versus organ-confined disease (25% versus 4%, P <0.05), pretreatment Gleason scores 7 or higher versus Gleason scores 6 or lower (11% versus 4%, P = NS), and pretreatment PSA levels higher than 10 microg/L compared with PSA levels lower than 10 microg/L (15% versus 0%, P <0.01). Overall PSA recurrence rate was 12.2% after a mean postoperative follow-up of 54 months. Risk of PSA recurrence increased with clinical stage (25% T3 versus 11% organ confined, P <0.01), pretreatment PSA (7% if PSA lower than 10 microg/L versus 21% if 10 microg/L or higher, P <0.02), Gleason score (9% if 6 or lower versus 22% if 7 or higher, P <0.02), and pathologic stage (6% of pT2, 24% of pT3M-, and 56% of pT3M+, P <0.01). PSA recurrences occurred in 6% of patients with no adverse preoperative risk factors, 12% with any one of the high-risk factors, and 29% with any two of the high-risk factors. CONCLUSIONS Risk of PSA recurrence after 8 months of neoadjuvant therapy is low after 5 years of follow-up and remains proportional to the presence of adverse preoperative risk factors. Prospective randomized studies are required to determine whether longer duration of neoadjuvant therapy reduces the risk of biochemical recurrence after radical prostatectomy.

The Significance of Prostatic Acid Phosphatase in Adenocarcinoma of the Prostate

Our radioimmunoassay for prostatic acid phosphatase was compared to commercial radioimmunoassay kits. A close correlation among all 3 assays was found in control groups, and in patients with benign prostatic hyperplasia and adenocarcinoma of the prostate. These results also were compared to recent reports from other centers using similar methodologies. In 7 to 15 per cent of the patients with bone metastasis normal levels of serum prostatic acid phosphatase were found. Variability in prostatic acid phosphatase production by the tumor may account for this finding. Elevated levels of prostatic acid phosphatase were associated more commonly with less differentiated primary tumors. A low percentage of prostatic acid phosphatase elevations in patients with early localized and incidental adenocarcinoma was found for the 3 assays evaluated. These factors, along with the falsely positive rates in patients with benign disease, limit severely the application of these assays to the screening of male patients at risk for adenocarcinoma of the prostate.

A Prospective Trial Comparing the Efficacy and Complications of the Modified Dornier HM3 and MFL 5000 Lithotriptors for Solitary Renal Calculi

A prospective randomized study of 198 patients was conducted to compare the efficacy of the modified Dornier HM3 lithotriptor to the MFL 5000 lithotriptor. Entrance criteria included solitary stones at any location within the upper collecting system that had not previously been treated with lithotripsy. Following lithotripsy the patients were evaluated by a blinded radiologist with a plain abdominal film, tomograms and renal ultrasound at 1, 4 and 12 weeks. Patients were classified at 12 weeks after lithotripsy as failing treatment if any stone fragments were imaged. Of the patients 170 were available for complete 3-month followup. No statistical or clinical difference in stone-free rates was apparent for calculi in the ureter or renal pelvis in either group. Of patients with lower caliceal stones 80% had no residual fragments visualized at 12 weeks when treated with the modified HM3 device versus 56% with the MFL 5000 lithotriptor (p = 0.05). Treatment time on the MFL 5000 unit was significantly prolonged compared with the modified HM3 device (0.7 hours versus 0.4 hours, respectively) resulting in fewer patients being treated in a given day (p < 0.001). No statistical difference in complication rates could be found between the 2 machines. Steinstrasse were noted in 10% of the patients treated with the modified HM3 device and 6% of the MFL 5000 group. Subcapsular hematomas were noted in 4% of the MFL 5000 treatment arm compared to 1% in the modified HM3 group. Overall, the MFL 5000 lithotriptor was believed to offer no significant clinical advantage over the modified HM3 device in terms of lithotripsy efficacy, although the multifunctional table did offer more versatility for stone treatment. For a busy lithotripsy center, the modified HM3 lithotriptor is still the most efficacious.

Butyrate analogue, isobutyramide, inhibits tumor growth and time to androgen‐independent progression in the human prostate LNCaP tumor model

Progression to androgen independence remains the main obstacle to improving survival and quality of life in patients with advanced prostate cancer. Induction of differentiation may serve as a rational basis for prevention of progression to androgen independence by modulating gene expression activated by castration or upregulated during androgen‐independent progression. The objectives of this study were to characterize the in vitro effects of sodium butyrate on human prostate cancer cell growth, PSA gene expression, and differentiation in the LNCaP tumor model and to determine whether tumor progression in vivo is delayed by isobutyramide, an orally bioavailable butyrate analogue with a longer half‐life. The effects of isobutyramide on LNCaP tumor growth and serum PSA levels in both intact and castrate male mice were compared to controls. At concentrations > 1 mM, butyrate induced dose‐dependent changes towards a more differentiated phenotype, G1 cell cycle arrest, and an 80% decrease in LNCaP cell growth rates. PSA gene expression was increased threefold by butyrate, indicative of differentiation‐enhanced gene expression. The half‐life of isobutyramide in athymic mice was determined by gas chromatography to be 4 h. During a 4 week period in intact‐placebo mice, tumor volume and serum PSA increased 4.1‐ and 6.6‐fold, respectively, compared to twofold and 2.7‐fold increases in tumor volume and serum PSA in intact‐treated mice. During a 7 week period in castrate‐placebo mice, tumor volume and serum PSA levels increased 2.4‐fold and fourfold, respectively, compared to a 50% reduction in tumor volume and a twofold increase in serum PSA above nadir levels in castrate mice treated with adjuvant isobutyramide. Isobutyramide treatment induced pronouced morphological changes in LNCaP tumor cells, with loss of defined nucleoli and dispersion of chromatin distribution. LNCaP tumor PSA mRNA levels actually increased threefold, indicative of differentiation‐enhanced gene expression. This study demonstrates that butyrate causes LNCaP cell cycle arrest and increased PSA gene expression, both indicative of differentiation. The combination of castration and adjuvant isobutyramide was synergistic in delaying tumor progression. Decreased tumor cell proliferation and increased PSA gene expression induced by isobutyramide results in disconcordant changes in serum PSA and tumor volume and reduces the utility of serum PSA as a marker of response to therapy. J. Cell. Biochem. 69:271–281, 1998.

Intratesticular Leiomyoma: A Case Report with Discussion of Differential Diagnosis and Histogenesis

A subcapsular intratesticular leiomyoma is described in a 65-year-old man. The pathology is discussed in detail and the hypothesis is advanced that the tumor arises from the myoid cells of the tunica propria of the seiminiferous tubules.

Teratoma in primary testis tumor reduces complete response rates in the retroperitoneum after primary chemotherapy

Recent advances in the therapy of advanced testicular nonseminomatous germ cell tumors (NSGCT) have resulted in increased attention to avoiding double therapy in cases where single modality therapy will suffice.