Management of clinically localized prostate cancer

Critics of screening have stated that early detection of prostate cancer does not necessarily reflect a diminishing death rate from the disease. However, several recent reports have demonstrated that the death rate from prostate cancer is decreasing, representing the most compelling validation for aggressive screening. Prostate cancer can be halted only if there is no evidence of systemic or regional metastases and the disease is confined to the surgical field or the radiation template. Surgeons and radiation oncologists must make a concerted effort to exclude men with regional and systemic metastases who are unlikely to benefit from treatment. With the widespread acceptance of prostate-specific antigen screening, a greater proportion of men are being diagnosed with clinically localized prostate cancer. Both radical prostatectomy and radiation therapy are able to halt disease spread in this significant subset of men, but survival outcomes indicate that radical prostatectomy is a more reliable treatment than radiation therapy for clinically localized prostate cancer. Overall, the immediate treatment-related morbidity of radical prostatectomy and radiation therapy in the modern era is quite low. Radical prostatectomy and radiation therapy appear to have a similar impact on continence and erectile function. There is a need for neoadjuvant and adjuvant therapies that can be utilized in those cases where radical prostatectomy and radiation are less likely to completely eradicate or destroy the cancer.     

Prostate cancer in elderly men

Due to increasing life expectancy and the introduction of prostate-specific antigen (PSA) screening, a rising number of elderly men are diagnosed with prostate cancer. Besides PSA serum levels and Gleason score, age is considered to be a key prognostic factor in terms of treatment decisions. In men older than 70 years, treatment without curative intent may deprive the frail patient of years of life. Modern radical prostatectomy techniques are associated with low perioperative morbidity, excellent clinical outcome, and documented long-term disease control. Thus, radical prostatectomy should be considered because local treatment of organ-confined prostate cancer potentially cures disease. The huge extent of PSA screening programs may lead to overdiagnosis of prostate cancer. Not every man who is diagnosed with prostate cancer will develop clinically significant disease. This has led to the concept of expectant management for screen-detected, small-volume, low-grade disease, with the intention of providing therapy for those men with disease progression.     

Current Clinical Applications of the In-capromab Pendetide Scan (ProstaScint(R) Scan, Cyt-356)

Prostate-specific antigen (PSA) has been extremely helpful in the detection of new or recurrent prostate cancer. However, localization of the recurrent tumor has been challenging with currently available radiographic modalities. The (111)In-capromab pendetide scan was developed to diagnose accurately and, more importantly, localize and stage a new or recurrent prostate cancer. Studies suggest that the (111)In-capromab pendetide scan can provide more accurate staging of clinically localized prostate cancer prior to staging lymphadenectomy or definitive therapy. It can also provide valuable information when local adjuvant radiation therapy is considered in men with biochemical cancer recurrence following radical prostatectomy.     

Selecting treatment for high-risk, localized prostate cancer: the case for radical prostatectomy

The most common treatment options for men with clinically localized prostate cancer include radical prostatectomy and radiation therapy. The choice between these options is often controversial, and selecting the optimal treatment poses a great challenge for patients and physicians. Factors important to the decision include age and life expectancy of the patient, the natural history of the prostate cancer, how curable the disease is, and the morbidity of treatment. Use of these criteria to select treatment for a healthy, 70-year-old man presenting with a nonpalpable tumor, stage T1c disease, serum prostate-specific antigen of 12 ng/mL, and an adenocarcinoma with a Gleason score of 8 that is present in 2 of 12 biopsy cores would lead to the choice of radical prostatectomy over radiation therapy. Data show that such a patient has a life expectancy of more than 12.3 years if the prostate cancer can be cured and a high probability of dying from the disease if it is not cured. Data further show that radical prostatectomy in such a patient would confer a survival advantage over radiation therapy without resulting in greater complications or reduction in quality of life.     

Minimally Invasive Therapy for Prostate Cancer: Use of Nomograms to Counsel Patients about the Choice and Probable Outcome of Therapy

Despite dramatic and recently accelerated advances in the reduction of morbidity linked to radical prostatectomies, significant short- and long-term morbidity is still associated with this surgical procedure. Currently both surgical and nonsurgical minimally invasive options are available for men with clinically localized prostate cancer, including laparoscopic and robotic radical prostatectomy, brachytherapy, and cryosurgical ablation of the prostate, with others, such as high intensity focused ultrasound, under investigation. In continued efforts to improve patient outcomes and to tailor treatment options to individual patient circumstances, nomograms have been developed and are increasingly being used by physicians and patients, alike, to guide therapeutic choices at each stage of disease. This tool predicts the possibility of successful treatment for the patient based on factors such as prostate-specific antigen levels, clinical stage of disease, and biopsy results. The current and future development, design, availability, and use of nomograms is described along with the historic and newer minimally invasive treatment options for prostate cancer.     

High Lysyl Oxidase (LOX) in the Non-Malignant Prostate Epithelium Predicts a Poor Outcome in Prostate Cancer Patient Managed by Watchful Waiting

Lysyl oxidase (LOX) has been shown to both promote and suppress tumor progression, but its role in prostate cancer is largely unknown. LOX immunoreactivity was scored in prostate tumor epithelium, tumor stroma and in the tumor-adjacent non-malignant prostate epithelium and stroma. LOX scores in tumor and non-malignant prostate tissues were then examined for possible associations with clinical characteristics and survival in a historical cohort of men that were diagnosed with prostate cancer at transurethral resection and followed by watchful waiting. Men with a low LOX score in the non-malignant prostate epithelium had significantly longer cancer specific survival than men with a high score. Furthermore, LOX score in non-malignant prostate epithelium remained prognostic in a multivariable analysis including Gleason score. LOX score in prostate tumor epithelium positively correlated to Gleason score and metastases but was not associated with cancer survival. LOX score in tumor and non-malignant prostate stroma appeared unrelated to these tumor characteristics. In radical prostatectomy specimens, LOX immune-staining corresponded to LOX in-situ hybridization and LOX mRNA levels were found to be similar between tumor and adjacent non-malignant areas, but significantly increased in bone metastases samples. LOX levels both in tumors and in the surrounding tumor-bearing organ are apparently related to prostate cancer aggressiveness.     

New techniques and management options for localized prostate cancer

Prostate cancer is diagnosed in younger men who want treatment that does not compromise their quality of life, take time away from work, or cause worrisome side effects. Laparoscopic radical prostatectomy, robot-assisted laparoscopic radical prostatectomy, and third-generation cryotherapy are modifications of previously used techniques in the treatment of prostate cancer and are presented in this article. Although some or all of the outcomes might be expected to change in the future, the urologic surgeon is left to select an approach, presumably on the basis of the experience, level of training, and care pathways at his or her institution.     

Prognostic values of morphological and clinical parameters in pT2-pT3 prostate cancer in elderly people

Prostate cancer is a disease of elderly men, the incidence of which increases in an age dependent manner. This study presents the correlation of clinical and morphological parameters in locally confined (pT2) and locally advanced (pT3) prostate cancer. We analyzed a group of elderly men treated with radical prostatectomy in the period 1999-2008 in the University Hospital Rijeka. We found no statistical association between pT stage and age categories, preoperative prostate-specific antigen, digitorectal examination and biopsy Gleason score. There was a significant correlation of higher Gleason score in prostate specimens after radical prostatectomy and a higher frequency of a positive surgical margin in tumors with pT3 than in pT2 stage (p = 0.003; p = 0.011 respectively). Recurrence-free survival was shorter in patients with tumors with positive surgical margins as well as in patients with pT3 stage (p = 0.030; p = 0.001 respectively). We conclude that higher tumor grade and positive surgical margins are indicators of a worse prognosis in our patients.     

Cavernous nerve reconstruction to preserve erectile function following non-nerve-sparing radical retropubic prostatectomy: a prospective study

Erectile dysfunction following radical prostatectomy for treatment of clinically localized prostate cancer remains a problem that deters many men from seeking surgical treatment. Sparing the cavernous nerves has been popularized as a method of preserving potency, but men with locally advanced disease may be at increased risk for positive margins with this technique. In this study, sural nerve grafting of the cavernous nerve bundles, to preserve postoperative potency while potentially maximizing cancer control, was examined. Thirty men were enrolled in this prospective phase I study and underwent non-nerve-sparing radical prostatectomy performed by one of two protocol surgeons. Preoperative erectile function was assessed both objectively, using a RigiScan (Timm Medical Technologies, Inc., Eden Prairie, Minn.), and subjectively. The cavernous nerves were identified and resected during the operation with the use of an intraoperative mapping device (CaverMap; Alliant Medical Technologies, Norwood, Mass.). Bilateral autologous sural nerve grafting to the cavernous nerve stumps was performed by one of two protocol plastic surgeons. Postoperative erectile dysfunction therapy, using intracorporeal injection, a vacuum pump, and/or oral sildenafil therapy, was instituted 6 weeks after the operation. Spontaneous erectile activity was subjectively and objectively measured every 3 months after the operation. Follow-up periods ranged from 13 to 33 months (mean, 23 months). Overall, 18 of 30 patients (60 percent) demonstrated both objective and subjective evidence of spontaneous erectile activity. Of those 18 men, 13 (72 percent) were able to have intercourse (seven unassisted and six with the aid of sildenafil). No disease or biochemical recurrences have been noted in this group of patients with locally advanced disease. In conclusion, autologous sural nerve grafting after non-nerve-sparing radical prostatectomy is an effective means of preserving spontaneous erectile activity after the operation while maximizing cancer control potential.     

CD44 and PTGS2 Methylation are Independent Prognostic Markers for Biochemical Recurrence Among Prostate Cancer Patients with Clinically Localized Disease

Up to 30% of men with clinically localized disease who receive radical prostatectomy develop a biochemical recurrence. Gene methylation in tumor tissue may distinguish men with aggressive cancer. This study evaluated methylation of GSTP1, RARβ2, CD44 and PTGS2 with biochemical recurrence among 60 patients who underwent radical prostatectomy using logistic regression and Kaplan Meier time to event analysis. Methylation of GSTP1 and RARβ2 was not associated with recurrence, however, CD44 and PTGS2 methylation were significant predictors. In multivariate models adjusting for Gleason grade, methylation profile of CD44 and PTGS2 combined was an independent predictor of biochemical recurrence (associated with 9-fold increased risk). In addition, Kaplan Meier analysis showed CD44 and PTGS2 methylation was associated with shorter time to recurrence. CD44 and PTGS2 methylation may predict biochemical recurrence in prostate cancer patients undergoing radical prostatectomy and if validated in larger studies, may identify patients with aggressive cancer.     

Changes in prostate cancer at radical prostatectomy during the prostate specific antigen era: an Italian experience

OBJECTIVE: To assess changes in prostate cancer clinical and pathologic features by review of 15 years' experience with radical prostatectomy. STUDY DESIGN: A total of 596 consecutive patients who underwent open or laparoscopic radical prostatectomy (RP) between 1991 and 2006 were included. All had clinically localized prostate cancer. Surgical specimens were analyzed or blindly reviewed by a uropathologist, and whole-mount sections were prepared. Statistical analysis evaluated whether significant changes in clinical and pathologic variables occurred over time. RESULTS: Median prostate specific antigen (PSA) values at diagnosis significantly decreased over time. Definite stage migration was observed, with significant increase of organ-confined tumors. Incidence of seminal vesicle and lymph node involvement declined steadily. Median tumor volume decreased significantly over time (p<0.001). Incidence of nonsignificant cancers at RP increased significantly, reaching 25.6% in 2006. PSA value has progressively lost correlation with prostate cancer volume and today correlates only with prostate gland volume. CONCLUSION: Prostate cancer stage and volume at diagnosis have steadily decreased in the last 15 years, likely reflecting increasing use of PSA testing. In early prostate cancer, PSA level no longer correlates with tumor volume.     

Success and failure of single-modality treatment for early prostate cancer

Many men who undergo radical prostatectomy or radiotherapy for early prostate cancer have an excellent outcome; however, a significant proportion subsequently experience disease recurrence and/or cancer-related death. Adjuvant hormonal therapy after treatment of curative intent is given with the aim of eradicating undetected cancer cells outside the surgical margins or radiation field and/or micrometastatic disease. In the analogous setting of early breast cancer, adjuvant hormonal therapy is already established as standard care. Efficacy and tolerability data from the ongoing bicalutamide ('Casodex') Early Prostate Cancer program are expected to determine the role of adjuvant hormonal therapy with antiandrogens in early prostate cancer.     

DNA methylation profiles in African American prostate cancer patients in relation to disease progression

This study examined whether differential DNA methylation is associated with clinical features of more aggressive disease at diagnosis and prostate cancer recurrence in African American men, who are more likely to die from prostate cancer than other populations. Tumor tissues from 76 African Americans diagnosed with prostate cancer who had radical prostatectomy as their primary treatment were profiled for epigenome-wide DNA methylation levels. Long-term follow-up identified 19 patients with prostate cancer recurrence. Twenty-three CpGs were differentially methylated (FDR q ≤ 0.25, mean methylation difference ≥ 0.10) in patients with vs. without recurrence, including CpGs in GCK, CDKL2, PRDM13, and ZFR2. Methylation differences were also observed between men with metastatic-lethal prostate cancer vs. no recurrence (five CpGs), regional vs. local pathological stage (two CpGs), and higher vs. lower tumor aggressiveness (one CpG). These results indicate that differentially methylated CpG sites identified in tumor tissues of African American men may contribute to prostate cancer aggressiveness.     

Abberant methylation of p16, HIC1, N33 and GSTP1 genes in tumor epitelium and tumor-associated stromal cells of prostate cancer

The methylation status of four genes significant in prostate carcinogenesis p16, HIC1, N33 and GSTP1, were evaluated using quantitative methylationsensitive polymerase chain reaction. Tumor epithelia, tumor-associated stroma, normal epithelia, foci of PIN and benign prostate hyperplasia, and stroma adjacent to tumor tissues were isolated from whole-mount prostatectomy specimens of patients with localized prostate cancer by using laser capture microdissection. We found high levels of gene methylation in the tumor epithelium and tumor-associated stromal cells and some methylation in both hyperplastic epithelium and stromal cells in normal-appearing tissues located adjacent to tumors. Promoter methylation in the non-neoplastic cells of the prostate tumor microenvironment may play an important role in cancer development and progression. We examined the promoter methylation status of pl6, HIC1, N33 and GSTP1 in prostate biopsy fragments and prostate tissues after radical prostatectomy from patients with adenocarcinoma without laser capture microdissection. Methylation frequencies of all genes in tumor samples were considerably lower than frequencies in microdissected tumour samples (HIC1, 71 versus 89%; p16, 22 versus 78%; GSTP1, 32 versus 100%; N33, 20 versus 33%). The laser capture microdissection is required procedure in methylation studies taking into account multifocality and heterogenity of prostate cancer tissue.     

MAGE-C2/CT10 protein expression is an independent predictor of recurrence in prostate cancer

The cancer-testis (CT) family of antigens is expressed in a variety of malignant neoplasms. In most cases, no CT antigen is found in normal tissues, except in testis, making them ideal targets for cancer immunotherapy. A comprehensive analysis of CT antigen expression has not yet been reported in prostate cancer. MAGE-C2/CT-10 is a novel CT antigen. The objective of this study was to analyze extent and prognostic significance of MAGE-C2/CT10 protein expression in prostate cancer. 348 prostate carcinomas from consecutive radical prostatectomies, 29 castration-refractory prostate cancer, 46 metastases, and 45 benign hyperplasias were immunohistochemically analyzed for MAGE-C2/CT10 expression using tissue microarrays. Nuclear MAGE-C2/CT10 expression was identified in only 3.3% primary prostate carcinomas. MAGE-C2/CT10 protein expression was significantly more frequent in metastatic (16.3% positivity) and castration-resistant prostate cancer (17% positivity; p<0.001). Nuclear MAGE-C2/CT10 expression was identified as predictor of biochemical recurrence after radical prostatectomy (p = 0.015), which was independent of preoperative PSA, Gleason score, tumor stage, and surgical margin status in multivariate analysis (p<0.05). MAGE-C2/CT10 expression in prostate cancer correlates with the degree of malignancy and indicates a higher risk for biochemical recurrence after radical prostatectomy. Further, the results suggest MAGE-C2/CT10 as a potential target for adjuvant and palliative immunotherapy in patients with prostate cancer.     

CARCINOMA OF THE PROSTATE—Diagnosis and Treatment

About 28 per cent of men between the ages of 71 and 75 have cancer of the prostate. Many of them do not die of the disease, but with the life span ever increasing, this problem is becoming more important.In the early stages the condition is asymptomatic; when the symptoms of urinary obstruction arise, the cancer is usually too advanced for cure. Cure depends on early diagnosis and, therefore, on routine rectal examination. The solitary hard nodule of early prostatic cancer becomes a stony hard fixed prostate as the condition progresses. X-ray and acid phosphatase studies are of help only after the cancer has metastasized. As many as 50 per cent of patients with rectally palpable early carcinoma of the prostate can be cured by radical perineal prostatectomy. Often, simple enucleation or transurethral resection is sufficient to effect cure in the case of occult carcinoma. However, some observers believe that when cancer is detected by microscopic examination of a prostate that has been removed, a radical operation should be done as soon after the initial operation as feasible. Early orchidectomy and estrogen therapy are of considerable help in slowing the process of advanced prostatic cancer and may postpone the need of transurethral resection to relieve obstruction. When these measures fail, bilateral adrenalectomy, cortisone therapy, pituitary irradiation, and pituitary extirpation have been employed, with moderate success, in an effort to diminish the androgen level.     

Carcinoma of the prostate; diagnosis and treatment

About 28 per cent of men between the ages of 71 and 75 have cancer of the prostate. Many of them do not die of the disease, but with the life span ever increasing, this problem is becoming more important. In the early stages the condition is asymptomatic; when the symptoms of urinary obstruction arise, the cancer is usually too advanced for cure. Cure depends on early diagnosis and, therefore, on routine rectal examination. The solitary hard nodule of early prostatic cancer becomes a stony hard fixed prostate as the condition progresses. X-ray and acid phosphatase studies are of help only after the cancer has metastasized. As many as 50 per cent of patients with rectally palpable early carcinoma of the prostate can be cured by radical perineal prostatectomy. Often, simple enucleation or transurethral resection is sufficient to effect cure in the case of occult carcinoma. However, some observers believe that when cancer is detected by microscopic examination of a prostate that has been removed, a radical operation should be done as soon after the initial operation as feasible. Early orchidectomy and estrogen therapy are of considerable help in slowing the process of advanced prostatic cancer and may postpone the need of transurethral resection to relieve obstruction. When these measures fail, bilateral adrenalectomy, cortisone therapy, pituitary irradiation, and pituitary extirpation have been employed, with moderate success, in an effort to diminish the androgen level.     

The Use of Vacuum Erection Devices in Erectile Dysfunction After Radical Prostatectomy

The risk of postoperative erectile dysfunction (ED) following radical prostatectomy (RP) is reported to be between 14% and 89%. With an increase in the detection of prostate cancer in younger men, there is a greater emphasis on the appropriate management of ED following RP. A number of options are available to manage ED after RP, including phosphodiesterase-5 inhibitors, intracorporeal injections, intraurethral alprostadil, and vacuum erection devices (VEDs). Penile rehabilitation programs are increasingly used to facilitate the return of natural postoperative erections; the VED is an ideal therapy given that it increases blood flow and oxygenation to the corpora to reverse the changes that result in ED after RP.Key words: Erectile dysfunction, Radical prostatectomy, Vacuum erection device, Penile rehabilitationProstate cancer is the most common cancer in men over the age of 50 years.¹ When patients undergo a radical prostatectomy (RP), there is a risk of postoperative erectile dysfunction (ED). The incidence of ED following RP has been reported to be between 14% and 89%.² With an increase in the detection of prostate cancer in younger men, there is a greater emphasis on the appropriate management of ED after RP. With an early diagnosis of prostate cancer, there is an increase in the rate of RP in younger men and the importance of ED as a quality-of-life issue has subsequently increased.² There are a number of options available to manage ED after RP, including phosphodiesterase-5 (PDE-5) inhibitors, intracorporeal injections, intraurethral alprostadil, and vacuum erection devices (VEDs). Despite highly reported satisfaction and efficacy with VEDs, there is a move by some medical practitioners away from VEDs due to cost. But what evidence is there for VED success after prostatectomy and what role do VEDs have in penile rehabilitation after ED? We present current evidence and provide our recommendations based on the latest literature.     

Prostate cancer risk in testosterone-treated men

Men with classical androgen deficiency have reduced prostate volume and blood prostate-specific antigen (PSA) levels compared with their age peers. As it is plausible that androgen deficiency partially protects against prostate disease, and that restoring androgen exposure increases risk to that of eugonadal men of the same age, men using ART should have age-appropriate surveillance for prostate disease. This should comprise rectal examination and blood PSA measurement at regular intervals (determined by age and family history) according to the recommendations, permanently revisited, published by ISSAM, EAU, Endocrine Society….

Testosterone replacement therapy is now being prescribed more often for aging men, the same population in which prostate cancer incidence increases; it has been suggested that administration in men with unrecognised prostate cancer might promote the development of clinically significant disease. In hypogonadal men who were candidates for testosterone therapy, a 14% incidence of occult cancer was found. A percentage (15.2%) of prostate cancer has been found in the placebo group (with normal DRE and PSA) in the prostate cancer prevention study investigating the chemoprevention potential of finasteride.

The hypothesis that high levels of circulating androgens is a risk factor for prostate cancer is supported by the dramatic regression, after castration, of tumour symptoms in men with advanced prostate cancer. However these effects, seen at a very late stage of cancer development, may not be relevant to reflect the effects of variations within a physiological range at an earlier stage.

Data from all published prospective studies on circulating level of total and free testosterone do not support the hypothesis that high levels of circulating androgens are associated with an increased risk of prostate cancer. A study on a large prospective cohort of 10,049 men, contributes to the gathering evidence that the long standing “androgen hypothesis” of increasing risk with increasing androgen levels can be rejected, suggesting instead that high levels within the reference range of androgens, estrogens and adrenal androgens decrease aggressive prostate cancer risk. Indeed, high-grade prostate cancer has been associated with low plasma level of testosterone. Furthermore, pre-treatment total testosterone was an independent predictor of extraprostatic disease in patients with localized prostate cancer; as testosterone decreases, patients have an increased likelihood of non-organ confined disease and low serum testosterone levels are associated with positive surgical margins in radical retropubic prostatectomy.

A clinical implication of these results concerns androgen supplementation which has become easier to administer with the advent of transdermal preparations (patch or gel) that achieve physiological testosterone serum levels without supra physiological escape levels. During the clinical development of a new testosterone patch in more than 200 primary or secondary hypogonadal patients, no prostate cancer was diagnosed.