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.     

A review of surgical techniques for radical prostatectomy

Since the early 20th century, radical prostatectomy has been used in the treatment of prostate cancer. However, before the widespread acceptance of prostate-specific antigen screening, the majority of cancers were clinically advanced and not amenable to cure, so relatively few men were candidates for this procedure. Modern advances have contributed dramatically to the reduction of complications and morbidity associated with radical prostatectomy. As a result, the procedure has become the most common treatment selected by men with localized prostate cancer. This article reviews several issues regarding radical prostatectomy, including surgical techniques, cancer control, intraoperative localization of the cavernous nerves, patient selection, and laparoscopic versus robotic approaches.     

Clinical experience with gene therapy for the treatment of prostate cancer

Localized prostate cancer can be treated effectively with radical prostatectomy or radiation therapy. The treatment options for metastatic prostate cancer are limited to hormonal therapy; hormone-refractory cancer is treated with taxane-based chemotherapy, which provides only a modest survival benefit. New treatments are needed. The gene for the initiation of prostate cancer has not been identified; however, gene therapy can involve tumor injection of a gene to kill cells, systemic gene delivery to target and kill metastases, or local gene expression intended to generate a systemic response. This review will provide an overview of the various strategies of cancer gene therapy, focusing on those that have gone to clinical trial, detailing clinical experience in prostate cancer patients.     

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.     

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.     

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.     

Selecting candidates for radical prostatectomy

Men with clinically localized prostate cancer and their physicians are faced with the management decision of radical prostatectomy, radiation therapy, or watchful waiting. Who is the best candidate for radical prostatectomy? Is cure the only relevant outcomes parameter? Does age make a difference? Are imaging studies necessary? This review provides answers, step-by-step, in the decision-making process.     

High-risk, clinically localized prostate cancer: is monotherapy adequate?

High-risk, clinically localized prostate cancer represents a diverse disease entity. Patients who are considered to be at highest risk for biochemical failure after localized treatments may not be at significant risk for disea-sespecific mortality. In this review, an attempt will be made to define high-risk status and help identify patients at high risk for mortality after a diagnosis of localized prostate cancer. Subsequently, a review of monotherapy approaches as well as previously successful strategies utilizing multimodality therapy for high-risk disease will be presented. Finally, a synopsis will be given of several ongoing randomized clinical trials using the most effective systemic therapies in the adjuvant setting following thorough local treatments such as radical prostatectomy. This review will provide a glimpse into the future and describe the tools that it is hoped will improve further upon the results of surgical monotherapy for high-risk, localized prostate cancer.     

Cancer de la prostate : la maladie localisée

Localized prostate cancer is characterized by a tumor confined to the prostate gland at clinical evaluation. Since the onset of PSA screening, the detection of localized prostate cancer has increased. Prognosis factors are clinical stadification, PSA value, PSA doubling time, tumor volume related to needle biopsy pathologic findings (Gleason score, percentage biopsies involved). Treatment depends on tumor prognosis, symptoms and performance status of the patient. Localized prostate cancer can be treated by surgery (radical prostatectomy, high intensity focused ultrasound) or radiotherapy (conformational radiation therapy, brachytherapy). Active follow-up can be proposed to very low risk patients.     

Vascular Targeted Photodynamic Therapy for Localized Prostate Cancer

Survival for men diagnosed with prostate cancer directly depends on the stage and grade of the disease at diagnosis. Prostate cancer screening has greatly increased the ability to diagnose small and low-grade cancers that are amenable to cure. However, widespread prostate-specific antigen screening exposes many men with low-risk cancers to unnecessary complications associated with treatment for localized disease without any survival advantage. One challenge for urological surgeons is to develop effective treatment options for low-risk disease that are associated with fewer complications. Minimally invasive ablative treatments for localized prostate cancer are under development and may represent a preferred option for men with low-risk disease who want to balance the risks and benefits of treatment. Vascular targeted photodynamic therapy (VTP) is a novel technique that is being developed for treating prostate cancer. Recent advances in photodynamic therapy have led to the development of photosynthesizers that are retained by the vascular system, which provides the opportunity to selectively ablate the prostate with minimal collateral damage to other structures. The rapid clearance of these new agents negates the need to avoid exposure to sunlight for long periods. Presented herein are the rationale and preliminary data for VTP for localized prostate cancer.Key words: Prostate cancer, localized; Minimally invasive ablative treatment for prostate cancer; Photodynamic therapy; WST-09; WST-11; Vascular targeted photodynamic therapy; Padoporfin; Palladium bacteriopheophorbideProstate cancer represents the second most common cause of cancer-related deaths in American men; it is estimated that 27,000 men in the United States died from the disease in 2007.¹ Survival for men with prostate cancer directly depends on the stage and grade of the disease at the time of diagnosis.² These sobering mortality statistics and the more favorable prognosis associated with early detection provide the primary justification for prostate cancer screening, which is performed by measuring the level of serum prostate-specific antigen (PSA) and conducting a digital rectal examination (DRE). It is estimated that 50% of men over the age of 50 years are screened annually for prostate cancer.³Despite widespread acceptance, prostate cancer screening is debated,^4,5 and recommendations for prostate cancer screening are inconsistent. Screening protagonists emphasize that radical prostatectomy increases prostate cancer survival in men with localized disease,⁶ and that the recently observed progressive and significant decline in prostate cancer mortality rates is the direct result of PSA screening and aggressive intervention.⁷ Screening antagonists emphasize the indolent natural history of most prostate cancers detected by screening,⁸ and that the vast majority of men who are treated for prostate cancer do not recognize any survival advantage from early detection and are simply left suffering the ravages of treatment.⁹Both sides of the screening debate have valid arguments. In the absence of widespread screening, many men are denied an opportunity to cure their disease. These men will experience the otherwise preventable consequences of disease progression, which include the development of androgen-insensitive disease¹⁰ and death. However, widespread screening exposes many men to unnecessary complications associated with treatment for localized disease. The challenges are to identify and treat only those cancers that have the biological potential to cause serious and preventable consequences, or to develop treatment options that are associated with fewer complications.     

Treatment options after failure of radiation therapy-a review

Radioresistant or recurrent prostate cancer represents a serious health risk for approximately 20%-30% of patients treated with primary radiation therapy for clinically localized prostate cancer. The majority of patients exhibit large volume and poorly differentiated disease at the time of diagnosis, which limits the ability of salvage therapy to eradicate the cancer. Early detection with serum PSA monitoring and prostate needle biopsy following primary radiation therapy may identify residual adenocarcinoma at an earlier stage and increase the likelihood of successful salvage therapy. Radical prostatectomy, prostate cryoablation, and brachytherapy comprise the options for salvage treatment available for radiorecurrent prostate cancer. The goal of disease eradication must be balanced against the potential for serious treatment-related side effects. As a result, many patients receive noncurative therapy with androgen ablation despite the real risk of disease progression and mortality.     

Place de la prostatectomie radicale dans le traitement du cancer de prostate

The screening of the prostate cancer with PSA has dramatically modified the circumstances of diagnosis. Nowadays, most of the patients have a localized disease. The treatment is based on prognostic factors and the spreading of the tumor. If the cancer is localized, some treatments are available. Among them, the radical prostatectomy can be performed either laparoscopically or by an open approach. Surgical treatment of prostate cancer is proven to be an effective way to decrease the occurrence of locoregional extension and metastatic disease. It has been proven that it allowed diminishing the mortality in patients who have a life expectancy more than 10 years. The side effects of the radical prostatectomy consist of impotency and incontinence which can be rehabilitated. The treatment of locally advanced cancer is a controversial issue that can consist in surgery as a unique treatment or in a multimodal treatment. This text summaries the recommendations of the French association of Urology.     

Tissue biomarkers for prostate cancer radiation therapy

Prostate cancer is the most common cancer and second leading cause of cancer deaths among men in the United States. Most men have localized disease diagnosed following an elevated serum prostate specific antigen test for cancer screening purposes. Standard treatment options consist of surgery or definitive radiation therapy directed by clinical factors that are organized into risk stratification groups. Current clinical risk stratification systems are still insufficient to differentiate lethal from indolent disease. Similarly, a subset of men in poor risk groups need to be identified for more aggressive treatment and enrollment into clinical trials. Furthermore, these clinical tools are very limited in revealing information about the biologic pathways driving these different disease phenotypes and do not offer insights for novel treatments which are needed in men with poor-risk disease. We believe molecular biomarkers may serve to bridge these inadequacies of traditional clinical factors opening the door for personalized treatment approaches that would allow tailoring of treatment options to maximize therapeutic outcome. We review the current state of prognostic and predictive tissue-based molecular biomarkers which can be used to direct localized prostate cancer treatment decisions, specifically those implicated with definitive and salvage radiation therapy.     

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.     

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.     

Modern brachytherapy for localized prostate cancers: the northwest hospital (Seattle) experience

Modern ultrasound-guided prostate brachytherapy is rapidly changing the way localized prostate cancer is managed. With routine use of prostate-specific antigen screening, prostate cancer is being diagnosed in younger men, who are understandably concerned about the morbidity of radical treatments that may significantly decrease their quality of life. Numerous studies of prostate brachytherapy have shown the excellent disease control rates achieved while maintaining low levels of urinary and erectile difficulties. This report examines a modern implant method of brachytherapy; describes patient selection for brachytherapy, alone and in combination with external beam therapy; and presents results from a series of men followed for 12 years.     

Bicalutamide adjuvant to radical prostatectomy

Prostate cancer recurrence affects up to 50% of men in the first 10 years after radical prostatectomy for clinically localized disease. New treatment approaches that reduce this risk are needed. Current published data on the use of adjuvant hormonal therapy in the post-radical prostatectomy setting are limited. New data from the bicalutamide (Casodex) Early Prostate Cancer program show that bicalutamide 150 mg/d, given as immediate adjuvant treatment, produces clear benefits with respect to both progression-free survival and prostate-specific antigen progression when compared with standard management with radical prostatectomy. The greatest improvement of progression-free survival was observed in patient subgroups at highest risk.     

Evaluation and treatment of men with biochemical prostate-specific antigen recurrence following definitive therapy for clinically localized prostate cancer

Early detection and monitoring by serum prostate-specific antigen (PSA) measurement has increased the number of men presenting with potentially curable prostate cancer. Most will choose radical prostatectomy or some form of radiation therapy for treatment, but some will have evidence of biochemical disease recurrence following therapy, shown by a rising PSA level without other clinical evidence of disease. Radical prostatectomy involves the removal of all prostate tissue, causing the serum PSA to decline to undetectable levels within four to six weeks following surgery; a subsequent rise in the serum PSA to a detectable level indicates disease recurrence. Patients should be evaluated to assess whether rising PSA levels indicate local recurrence or early metastatic disease. The advantages of salvage radiation, endocrine therapy, and other treatment modalities in local disease recurrence must be weighed against potential side effects and the resulting decrease in quality of life. Radiation therapy does not immediately eradicate all PSA-producing cells; therefore the persistence of a detectable PSA does not necessarily imply residual cancer, but rising PSA levels indicate treatment failure. Salvage surgery can be performed after radiotherapy for the purpose of removing all viable cancer cells, but should be weighed against a higher incidence of surgical complications; cryoablation offers a less invasive therapeutic modality.     

Histopathological changes induced by therapies in the benign prostate and prostate adenocarcinoma

The effect of androgen deprivation and other hormonal therapies, radiation therapy, thermal ablation therapies, chemotherapy, and other systemic treatments is evident in the histology of non-neoplastic and neoplastic human prostate gland. Androgen deprivation may be achieved with: a. orchidectomy, b. exogenous oestrogen administration, c. drugs with the capacity to deplete the hypothalamus of luteinizing hormone-releasing hormone, d. antiandrogens administration: drugs, which block the conversion of testosterone to its active form of 5-alpha dihydrotestosterone (i.e. finasteride, dutasteride), and drugs which block the androgen receptor on individual cells (i.e. flutamide). Androgen deprivation therapies cause atrophy of non-neoplastic and neoplastic prostatic epithelium, as the result of apoptosis, and are mainly used as a palliative measure in metastatic prostate cancer or as neoadjuvant or adjuvant treatment, in clinically localized prostate cancer. Morphological tumour regression may complicate the recognition and grading of treated carcinomas in radical prostatectomy specimens. Radiation therapy may be applied in the form of external beam, interstitial implantation (brachytherapy), or a combination, as a mainstay or adjuvant (external beam) treatment in localized prostate cancer. The primary effect is the damage of endothelial cells, which cause ischemia that leads to atrophy. The difficulty of post-radiation prostate needle biopsy interpretation includes the distinction of treatment effect in normal prostatic tissue from recurrent or residual tumour. Histological changes after thermal ablation mainly include lesions observed in prostatic infarcts due to periurethral coagulative type necrosis of variable volume. The correlation between the histopathological effects of the above therapies and their clinical significance is not absolutely clear.     

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.