Mitchell S. Steiner

Impact of Anatomical Radical Prostatectomy on Urinary Continence

Urinary continence following an anatomical approach to radical prostatectomy was evaluated in 593 consecutive patients, 547 (92%) of whom achieved complete urinary control. Stress incontinence was present in 46 patients (8%), of whom 34 (6%) wore 1 or fewer pads per day and 2 (0.3%) required placement of an artificial sphincter. No patient was totally incontinent. Age, weight of the prostate, prior transurethral resection of the prostate, pathological stage and preservation or wide excision of the neurovascular bundles had no significant influence on preservation of urinary control. These data suggest that anatomical factors rather than preservation of autonomic innervation may be responsible for the improved urinary control associated with an anatomical approach to radical prostatectomy.

The natural history of renal angiomyolipoma

Of 35 patients with 48 angiomyolipomas 24 patients were followed clinically to determine the natural history of angiomyolipoma. Average patient age at presentation was 50 years (range 17 to 74) and of the patients 94% were women, 17% had tuberous sclerosis and 25% overall had bilateral disease. The patients could be divided into 2 distinct groups based on tumor size of 4 cm. or less and greater than 4 cm. Those with tumors less than 4 cm. were less likely to be symptomatic (24%) and patients with angiomyolipomas greater than 4 cm. were more often symptomatic (52%). No surgery was required for tumors less than 4 cm. but for 30% of the tumors greater than 4 cm. surgical intervention was necessary. Unlike any previously reported large series this study included radiological and historical followup available for 24 patients with angiomyolipoma with a mean followup time of 4 years (range 0.5 to 14). Moreover, to our knowledge we report for the first time documented growth during the study period of 27% of angiomyolipomas less than 4 cm. (4 of 15 tumors) and 46% of angiomyolipomas greater than 4 cm. (6 of 13 tumors). All patients with tumors less than 4 cm. were asymptomatic and only 1 required surgery. In contrast, tumors greater than 4 cm. were more frequently symptomatic (46%) and required surgery (54%). Patients with tuberous sclerosis and angiomyolipomas were distinctly different from patients with angiomyolipoma only, since they tended to present at a younger age, had a higher incidence of bilateral renal involvement, were more symptomatic, had larger tumors that were more likely to grow, and frequently required surgery. Based on this study, a modified approach to the current management of angiomyolipoma is recommended.

Muscle wasting in cancer cachexia: clinical implications, diagnosis, and emerging treatment strategies.

Cancer cachexia is a complex metabolic condition characterized by loss of skeletal muscle. Common clinical manifestations include muscle wasting, anemia, reduced caloric intake, and altered immune function, which contribute to increased disability, fatigue, diminished quality of life, and reduced survival. The prevalence of cachexia and the impact of this disorder on the patient and family underscore the need for effective management strategies. Dietary supplementation and appetite stimulation alone are inadequate to reverse the underlying metabolic abnormalities of cancer cachexia and have limited long-term impact on patient quality of life and survival. Therapies that can increase muscle mass and physical performance may be a promising option; however, there are currently no drugs approved for the prevention or treatment of cancer cachexia. Several agents are in clinical development, including anabolic agents, such as selective androgen receptor modulators and drugs targeting inflammatory cytokines that promote skeletal muscle catabolism.

NEUROANATOMY OF THE MALE RHABDOSPHINCTER

OBJECTIVES The external striated urethral sphincter (rhabdosphincter) is a tubular muscle sleeve that extends from the prostato-membranous urethra and perineal membrane to the bladder neck. The male rhabdosphincter neuroanatomy remains unclear, and a better understanding of its innervation may provide insight into potential modifications of radical pelvic surgery to improve urinary continence. METHODS Fresh cadaveric dissections of 12 male hemipelves were undertaken to investigate the neuroanatomy of the urinary rhabdosphincter. RESULTS Neuroanatomic courses of the nerve supply to the rhabdosphincter revealed that, in the perineum, the perineal nerve (a terminal branch of the pudendal nerve) provided branches directly to the bulbospongiosus muscle and the urinary rhabdosphincter. In the pelvis, the course of the pelvic nerve was as follows: (1) arising from the inferior hypogastric plexus, it had a weblike course beneath the muscle fascia of the levator ani muscle; (2) traveling posterolateral to the rectum, it gave many branches that perforated into the lateral rectum; and (3) at the level of the prostatic apex, still beneath the levator ani muscle fascia (superior fascia), it sent multiple direct branches to the inferolateral aspect of urinary rhabdosphincter. The pudendal nerve traversed the pelvis in the pudendal canal, and, before leaving the pelvis to enter the perineum, it gave an intrapelvic branch that courses with the pelvic nerve to innervate the rhabdosphincter. CONCLUSIONS Our understanding of the neuroanatomy of what may be the continence nerves has been improved by fresh cadaveric dissection. The rhabdosphincter receives nerve fibers from the pelvic nerve and dual innervation from an intrapelvic branch and a perineal branch of the pudendal nerve. Better understanding of these anatomic findings may have potential surgical significance with respect to improvement in postoperative urinary continence.

Toremifene to Reduce Fracture Risk in Men Receiving Androgen Deprivation Therapy for Prostate Cancer

PURPOSE Androgen deprivation therapy is associated with fracture risk in men with prostate cancer. We assessed the effects of toremifene, a selective estrogen receptor modulator, on fracture incidence in men receiving androgen deprivation therapy during a 2-year period. MATERIALS AND METHODS In this double-blind, placebo controlled phase III study 646 men receiving androgen deprivation therapy for prostate cancer were assigned to toremifene (80 mg by mouth daily) and 638 were assigned to placebo. Subjects were followed for 2 years. The primary study end point was new vertebral fractures. Secondary end points included fragility fractures, bone mineral density and lipid changes. RESULTS The 2-year incidence of new vertebral fractures was 4.9% in the placebo group vs 2.5% in the toremifene group, a significant relative risk reduction of 50% (95% CI -1.5 to 75.0, p = 0.05). Toremifene significantly increased bone mineral density at the lumbar spine, hip and femoral neck vs placebo (p <0.0001 for all comparisons). There was a concomitant decrease in markers of bone turnover (p <0.05 for all comparisons). Toremifene also significantly improved lipid profiles. Venous thromboembolic events occurred more frequently with toremifene than placebo with 7 subjects (1.1%) in the placebo group experiencing a venous thromboembolic event vs 17 (2.6%) in the toremifene group. Other adverse events were similar between the groups. CONCLUSIONS Toremifene significantly decreased the incidence of new vertebral fractures in men receiving androgen deprivation therapy for prostate cancer. It also significantly improved bone mineral density, bone turnover markers and serum lipid profiles.

Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial

BACKGROUND Cancer-induced muscle wasting begins early in the course of a patients malignant disease, resulting in declining physical function and other detrimental clinical consequences. This randomised, double-blind, placebo-controlled phase 2 trial assessed the efficacy and safety of enobosarm, a selective androgen receptor modulator, in patients with cancer. METHODS We enrolled male (>45 years) and female (postmenopausal) patients with cancer who were not obese and who had at least 2% weight loss in the previous 6 months. Participants were randomly assigned (1:1:1 ratio, by computer generated list, block size three, stratified by cancer type) to receive once-daily oral enobosarm 1 mg, 3 mg, or placebo for up to 113 days at US and Argentinian oncology clinics. The sponsor, study personnel, and participants were masked to assignment. The primary endpoint was change in total lean body mass from baseline, assessed by dual-energy x-ray absorptiometry. Efficacy analyses were done only in patients who had a baseline and an on-treatment assessment in the protocol-specified window of within 10 days before baseline or first study drug, and within 10 days of day 113 or end of study (evaluable efficacy population). Adverse events and other safety measurements were assessed in the intention-to-treat (safety) population. This trial is registered with ClinicalTrials.gov, number NCT00467844. FINDINGS Enrolment started on July 3, 2007, and the last patient completed the trial on Aug 1, 2008. 159 patients were analysed for safety (placebo, n=52; enobosarm 1 mg, n=53; enobosarm 3 mg, n=54). The evaluable efficacy population included 100 participants (placebo, n=34; enobosarm 1 mg, n=32; enobosarm 3 mg, n=34). Compared with baseline, significant increases in total lean body mass by day 113 or end of study were noted in both enobosarm groups (enobosarm 1 mg median 1·5 kg, range -2·1 to 12·6, p=0·0012; enodosarm 3 mg 1·0 kg, -4·8 to 11·5, p=0·046). Change in total lean body mass within the placebo group (median 0·02 kg, range -5·8 to 6·7) was not significant (p=0·88). The most common serious adverse events were malignant neoplasm progression (eight of 52 [15%] with placebo vs five of 53 [9%] with enobosarm 1 mg vs seven of 54 [13%] with enobosarm 3 mg), pneumonia (two [4%] vs two [4%] vs three [6%]), and febrile neutropenia (three [6%vs one [2%] vs none). None of these events were deemed related to study drug. INTERPRETATION Cancer cachexia is an unmet medical need and our data suggest that use of enobosarm might lead to improvements in lean body mass, without the toxic effects associated with androgens and progestational agents. FUNDING GTx.

Cancer control following anatomical radical prostatectomy: an interim report.

Cancer control following anatomical radical prostatectomy was evaluated in 586 men who were followed for 1 1/2 to 8 years (median followup 4 years, 166 men followed 5 years or longer). The 5-year actuarial rate was 4% for local recurrence alone, 5% for distant metastases alone, 2% for distant metastases in association with local recurrence and 3% for death of or with disease, while 10% of the men had elevated levels of prostate specific antigen without local recurrence or distant metastases. When the actuarial status at 5 years was evaluated by clinical stage there was local recurrence alone in 0% of men with a clinical stage A1 or B1 nodule, and 4% with stage B1, 7% with stage A2 and 8% with stage B2 disease. When evaluated by pathological stage at 5 years local recurrence alone was noted in 2% of men with organ-confined disease, 8% with specimen-confined disease and 8% in whom the disease involved the surgical margin, seminal vesicles or pelvic lymph nodes. Recognizing that two-thirds to three-quarters of all local recurrences occur within the first 5 years, these data suggest that the anatomical approach to radical prostatectomy is associated with local control rates that are equal to or greater than other series reported in the literature. However, without a randomized study it is impossible to compare one clinical series to another, and followup evaluations at 10 and 15 years will be necessary to confirm these findings.

Prognostic factors in men with stage D1 prostate cancer: identification of patients less likely to have prolonged survival after radical prostatectomy.

The role of radical prostatectomy in the management of stage D1 disease is controversial. Although cure is unlikely, some men survive for long intervals apparently free of metastatic disease. For this reason, effective palliation of the local lesion is desirable in men who will live long enough to benefit. In an effort to identify factors that correlated with interval to progression to distant metastases, we studied 113 men with stage D1 disease who underwent radical prostatectomy between 1974 and 1991. Progression of disease to distant metastases did not independently correlate with the size of the nodal metastases, number of positive lymph nodes or bilaterality of lymph node metastases. Only high Gleason score (8 to 10) on the preoperative biopsy correlated with rapid progression to distant metastases (p < or = 0.00001) in a multivariate analysis. If the Gleason score was less than 8, the likelihood of distant metastases was only 18% and 41% at 5 and 10 years, respectively, whereas 85% of men with a Gleason score of 8 to 10 had distant metastases by 5 years. For urologists who believe that radical prostatectomy is useful in providing local control in men with positive lymph nodes, frozen section analysis of lymph nodes is probably not necessary in men who are candidates for radical prostatectomy and have preoperative Gleason scores of less than 8. Conversely, in patients with a Gleason score of 8 to 10 on needle biopsy, careful analysis of lymph nodes is necessary to avoid radical prostatectomy in those who will derive little benefit.

Toremifene Improves Lipid Profiles in Men Receiving Androgen-Deprivation Therapy for Prostate Cancer: Interim Analysis of a Multicenter Phase III Study

PURPOSE Androgen-deprivation therapy (ADT) is associated with greater risk of incident coronary heart disease and hospital admission for myocardial infarction; treatment-related increases in serum lipids may contribute to greater cardiovascular disease risk. We evaluated the effects of toremifene, a selective estrogen-receptor modulator, on fasting serum lipid levels in men receiving ADT for prostate cancer. PATIENTS AND METHODS In an ongoing, multicenter, double-blind, placebo-controlled phase III fracture-prevention study, 1,389 men receiving ADT for prostate cancer were randomly assigned to receive toremifene (80 mg/d) or placebo. In this interim analysis of 188 patients, changes in fasting serum lipids from baseline to month 12 were compared between the placebo and toremifene groups. RESULTS Changes in serum lipids differed significantly between the groups. Mean (+/- SE) total cholesterol decreased by 1.0% +/- 1.7% from baseline to month 12 in the placebo group and decreased by 8.1% +/- 1.4% in the toremifene group (P = .001 for between group comparison). Low-density lipoprotein (LDL) cholesterol increased by 0.8% +/- 2.5% in the placebo group and decreased by 8.2% +/- 2.5% in the toremifene group (P = .003). In contrast, high-density lipoprotein (HDL) cholesterol decreased by 4.9% +/- 1.2% in the placebo group and increased by 0.5% +/- 2.2% in the toremifene group (P = .018). Triglycerides increased by 6.9% +/- 4.2% in the placebo group and decreased by 13.2% +/- 3.6% in the toremifene group (P = .003). CONCLUSION Toremifene significantly decreased total cholesterol, LDL cholesterol, and triglycerides, and increased HDL cholesterol in men receiving ADT for prostate cancer.

Efficacy of first-generation Cavermap to verify location and function of cavernous nerves during radical prostatectomy: A multi-institutional evaluation by experienced surgeons

OBJECTIVES To evaluate, using five experienced surgeons, the efficacy of the first-generation Cavermap Surgical Aid to identify the cavernous nerves intraoperatively and to predict the recovery of sexual function. This study was not designed to determine whether this device improves the ability to preserve the nerves or improve outcome. METHODS Fifty men younger than 60 years old (mean age 52.5 years; range 43 to 59) with clinically localized prostate cancer (76% T1c, mean Gleason score 6, prostate-specific antigen level less than 10 ng/mL) underwent nerve-sparing radical prostatectomy (90% bilateral). Intraoperatively, the Cavermap device was used to test for the presence of the cavernous nerves once the neurovascular bundle was identified visually and to determine whether the nerves were intact after the prostate was removed. Erectile function was evaluated using the International Index of Erectile Function; men were considered potent if they were able to achieve unassisted intercourse in at least one half of their attempts. RESULTS Before the removal of the prostate, the tumescence response to stimulation of the neurovascular bundle was 87.8%; when tissue not containing the neurovascular bundle was stimulated, no tumescence response occurred in 54%. After prostatectomy, a bilateral response to stimulation occurred in 90%, a unilateral response in 5%, and no response in 5%. Postoperatively, 71% of the patients were potent at 12 months. In the patients who demonstrated bilateral stimulation after removal of the prostate, 78% were potent at 12 months. CONCLUSIONS After radical prostatectomy performed by experienced surgeons, patient-reported potency rates in men younger than 60 years of age were high. Cavermap stimulation demonstrated an 87.8% sensitivity and 54% specificity in locating the neurovascular bundle as identified by experienced surgeons. The lack of specificity of this first-generation device limits its application for deciding which structures can be safely preserved or excised. Because virtually all patients demonstrated a positive response after removal of the prostate, the value of stimulation to predict the recovery of sexual function is yet to be determined.