Experience with 125I brachytherapy as a radical treatment for prostate cancer at the Russian X-ray Radiology Research Center

Prostate cancer is one of the most common malignancies among males. 125I brachytherapy is a current, effective, comparatively safe, and easy-to-reproduce treatment. The Russian X-ray Radiology Research Center has implanted 125I microsources in patients with localized and locally advanced prostate cancer since 2003; 689 125I implantations were performed in the past year. Tumor-specific survival after brachytherapy did not differ greatly from that following radical prostatectomy. Thus, brachytherapy is a current high-tech treatment for prostate cancer. This therapy shows fewer adverse postradiation effects than radiation teletherapy.     

Advances in brachytherapy

During the past 15 years, permanent seed brachytherapy for prostate cancer has advanced significantly in all areas, including patient selection, treatment planning, technique, and technology (eg, seeds stranded in Vicryl suture). These improvements have made transperineal seed implantation an accurate and practical treatment option for men with low-, intermediate-, and high-risk disease. Because of the evidence that the various treatment options for prostate cancer are likely to be equally successful in terms of long-term cancer control, continuing efforts focus on enhancing the quality of life of implant patients.     

Acute myeloid leukemia incidence following radiation therapy for localized or locally advanced prostate adenocarcinoma

Introduction: The effect of radiation therapy on acute myeloid leukemia incidence among prostate cancer patients has not been sufficiently elucidated despite evidence that acute myeloid leukemia is a consequence of therapeutic radiation in other primary malignancies. Therefore, we investigated the effect of definitive therapy with radiation therapy (external beam radiation therapy [EBRT] or brachytherapy) on acute myeloid leukemia incidence in a population-based cohort of patients with localized or locally advanced prostate cancer. Methods: We utilized the Surveillance, Epidemiology, and End Results database to identify a cohort of men (n = 168,612) with newly diagnosed prostate adenocarcinoma between January 1988 and December 2003. Cox proportional hazard regression was used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) of acute myeloid leukemia incidence following definitive therapy with EBRT alone, brachytherapy alone, or surgery alone compared to no definitive therapy (i.e. no EBRT, brachytherapy, or surgery). Results: The cohort yielded 184 acute myeloid leukemia cases during 1,064,820 person-years of follow-up after prostate adenocarcinoma diagnosis. Patients treated with EBRT had a higher adjusted relative risk of developing acute myeloid leukemia than patients treated with brachytherapy or surgery when each therapy group was compared to patients who were not treated with definitive therapy (EBRT: HR = 2.05, 95% CI 1.29, 3.26; brachytherapy: HR = 1.22, 95% CI 0.46, 3.22; surgery: HR = 1.24, 95% CI 0.77, 1.98). Conclusions: Our findings suggest that acute myeloid leukemia incidence is a greater concern for patients treated with EBRT than brachytherapy for localized or locally advanced prostate adenocarcinoma.     

Long term results of HDR brachytherapy in men older than 75 with localized carcinoma of the prostate

Background

Prostate cancer is an illness with a high incidence, especially among older men. The choice of a treatment option among men above 75 years is, however, not clear. Radical prostatectomy in this age group is connected with a relatively high morbidity. A further possibility of curative treatment is radiotherapy which can be administered in the form of external beam or in combination with high dose rate (HDR) brachytherapy.

Aim

The aim of our work was to evaluate how HDR brachytherapy is tolerated among men older than 75 and how associated diseases can influence the tolerance to this treatment. Of interest to us were the treatment results and mortality from other diseases.

Materials and methods

We analyzed a sample of 20 men above 75 years old (median 77 years) who were undergoing treatment by a combination of external radiotherapy and brachytherapy. Sixteen (80%) of them had prostate cancer with an intermediate and high risk of recurrence, four had low risk prostate cancer. Most patients, 14 (70%), had less than two comorbidities.

Results

The median observation period was 57 months. No perioperative complications were recorded. Acute genitourinary toxicity (GU) to a maximum grade of 1–2 manifested in 60% of cases. Acute gastrointestinal toxicity (GIT) was observed only at grade 1 and in 25% of cases. Late GU toxicity occurred in 35% of patients, with only one showing grade 3; late GIT toxicity was recorded at grade 1 only in 3 patients (15%). 70% of the men lived longer than 3 years after treatment, at present, 50% lived more than 5 years. Long-term biochemical remission was achieved in 18 patients (90%).

Conclusions

HDR BRT is possible and well-tolerated in older men above 75 years in good condition and without serious intercurrence.Well-selected older patients with higher-risk tumours and without serious comorbidities undoubtedly benefit from radical treatment when compared with watchful waiting.     

Prostatic irradiation-induced sexual dysfunction: A review and multidisciplinary guide to management in the radical radiotherapy era (Part II on Urological Management)

Prostate cancer is the most common malignancy in men and the second leading cause of cancer-related death in men. Radiotherapy is a curative option that is administered via external beam radiation, brachytherapy, or in combination. Sexual dysfunction is a common toxicity following radiotherapy, similar to men undergoing radical prostatectomy, but the etiology is different. The pathophysiology of radiation-induced sexual dysfunction is multi-factorial, and the toxicity is a major cause of impaired quality of life among long-term prostate cancer survivors. Management of a patient’s sexual function during and after radiotherapy requires multidisciplinary coordination of care between radiation oncology, urology, psychiatry, pharmacy, and dermatology. This review provides a framework for clinicians to better understand prostatic radiotherapy-induced sexual dysfunction diagnosis, evaluation, and a patient-centered approach to toxicity preventive strategies and management.     

Permanent prostate brachytherapy: the significance of postimplant dosimetry

Recent developments in imaging science and treatment-planning software allow for accurate postimplant dosimetric assessment in all patients after prostate brachytherapy. This article reviews the available data correlating cancer control and morbidity with dosimetric quantifiers obtained from postimplant dosimetric assessment after prostate brachytherapy. Continued collection of dosimetric data in patients treated with prostate brachytherapy will allow for further refinements in the technique, leading to continued high rates of cure with increasingly lower rates of morbidity.     

Epidémiologie,diagnostic et pronostic du cancer de la prostate

Prostate cancer is the most frequent of cancers and represents the third leading cause of death by cancer, for men over 50 years, in France and Europe. The incidence decreases since about ten years. Mass screening is not recommended. Individual early diagnosis is based on a yearly exam including Prostate Specific Antigene (PSA) blood test and a digital rectal exam. The target for this diagnostic approach are men from 50 to 75 years with more than 10 years of life expectancy. A series of prostatic biopsy are carried out in case of clinical and/or biological prostate cancer suspicion. The additional examinations recommended in the assessment of extension of prostate cancer with intermediate and high risk are: MRI, bones scintigraphy, scan CAP (metastatic stage), and sometimes Choline PET-CT. Curative treatments are proposed to men with a probability of survival over 10 years, suffering from localized or locally advanced cancer. Gold standard treatments are: active surveillance, radical prostatectomy, brachytherapy, radiotherapy alone or with surgery and/or hormone therapy. Experimental treatments of localized tumors are: focal treatments (phototherapy dynamic, high intensity focused ultrasound). For the more advanced forms, the interest of early chemotherapy is extensively studied.     

Variations in prostate biopsy recommendation and acceptance confound evaluation of risk factors for prostate cancer: Examining race and BMI

BackgroundProstate cancer is ubiquitous in older men; differential screening patterns and variations in biopsy recommendations and acceptance will affect which man is diagnosed and, therefore, evaluation of cancer risk factors. We describe a statistical method to reduce prostate cancer detection bias among African American (n = 3398) and Non-Hispanic White men (n = 22,673) who participated in the Selenium and Vitamin E Cancer Prevention trial (SELECT) and revisit a previously reported association between race, obesity and prostate cancer risk.MethodsFor men with screening values suggesting prostate cancer but in whom biopsy was not performed, the Prostate Cancer Prevention Trial Risk Calculator was used to estimate probability of prostate cancer. Associations of body mass index (BMI) and race with incident prostate cancer were compared for observed versus imputation-enhanced outcomes using incident density ratios.ResultsAccounting for differential biopsy assessment, the previously reported positive linear trend between BMI and prostate cancer in African American men was not observed; no BMI association was found among Non-Hispanic White men.ConclusionsDifferential disease classification among men who may be recommended to undergo and then consider whether to accept a prostate biopsy leads to inaccurate identification of prostate cancer risk factors. Imputing a man’s prostate cancer status reduces detection bias. Covariate adjustment does not address the problem of outcome misclassification. Cohorts evaluating incident prostate cancer should collect longitudinal screening and biopsy data to adjust for this potential bias.     

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.     

Prostate Cancer Specificity of PCA3 Gene Testing: Examples from Clinical Practice

A specific marker for early prostate cancer would fill an important void. In initial evaluations of the prostate cancer antigen 3 (PCA3) gene vis-à-vis serum prostate-specific antigen (PSA) levels, the gene offers great promise. At the cellular level, PCA3 specificity for cancer is nearly perfect because of the gross overexpression of the gene by cancer cells. As a clinical test for early prostate cancer, heightened specificity is also seen in urine containing prostate cells from men with the disease. PCA3 gene testing holds valuable potential in PSA quandary situations: (1) men with elevated PSA levels but no cancer on initial biopsy; (2) men found to have cancer despite normal levels of PSA; (3) men with PSA elevations associated with varying degrees of prostatitis; and (4) men undergoing active surveillance for presumed microfocal disease.     

Penile Rehabilitation Strategies Among Prostate Cancer Survivors

Despite advances in technical and surgical approaches, erectile dysfunction (ED) remains the most common complication among prostate cancer survivors, adversely impacting quality of life. This article analyzes the concept and rationale of ED rehabilitation programs in prostate cancer patients. Emphasis is placed on the pathophysiology of ED after diagnosis and treatment of prostate cancer to understand the efficacy of rehabilitation programs in clinical practice. Available evidence shows that ED is a transient complication following prostate biopsy and cancer diagnosis, with no evidence to support rehabilitation programs in these patients. A small increase in ED and in the use of phosphodiesterase type 5 (PDE5) inhibitors was reported in patients under active surveillance. Patients should be advised that active surveillance is unlikely to severely affect erectile function, but clinically significant changes in sexual function are possible. Focal therapy could be an intermediate option for patients demanding treatment/refusing active surveillance and invested in maintaining sexual activity. Unlike radical prostatectomy, there is no support for PDE5 inhibitor use to prevent ED after highly conformal external radiotherapy or low-dose rate brachytherapy. Despite progress in the understanding of the pathophysiologic mechanisms responsible for ED in prostate cancer patients, the success rates of rehabilitation programs remain low in clinical practice. Alternative strategies to prevent ED appear warranted, with attention toward neuromodulation, nerve grafting, nerve preservation, stem cell therapy, investigation of neuroprotective interventions, and further refinements of radiotherapy dosing and delivery methods.Key words: Prostate cancer, Erectile dysfunction, Penile rehabilitation, Phosphodiesterase type 5 inhibitor, Prostaglandin E₁In the United States, prostate cancer is the most frequently diagnosed nonskin cancer in men, and is second only to lung cancer as a cause of cancer death.¹ In 2014, an estimated 233,000 men in the United States were diagnosed with a prostate cancer and 29,480 men were expected to die from their disease.² In the prostate-specific antigen (PSA) era, the importance of this type of cancer becomes evident when considering that more young, sexually active men are being diagnosed at an early stage while the tumor is still organ confined. Early detection of prostate cancer in the PSA era, as well as improvements in systemic treatment of metastatic prostate cancer, has led to an increased life expectancy; but cancer diagnosis and treatment carry serious physical and psychological consequences that can dramatically decrease quality of life.³ However, these results had recently drawn the attention of the scientific community to the quality of life of cancer survivors in order to promote health as defined by the World Health Organization (WHO).⁴ Despite advances in technical and surgical approach, erectile dysfunction (ED) remains the most common and the most documented complication among prostate cancer survivors, adversely impacting quality of life.⁵ ED is also a prevalent long-term complication among prostate cancer patients receiving systemic therapy.⁶ In recent years, investigators have increasingly focused on ED in prostate cancer patients. They have directed their efforts toward searching for interventions that might improve erectile function. Various coping strategies and rehabilitation programs have been suggested and applied with different success rates.This article provides an overview of the literature, analyzing the concept and rationale of rehabilitation programs for ED in prostate cancer patients. Emphasis is placed on the pathophysiology of such disorders after diagnosis and treatment of prostate cancer in order to understand the efficacy of rehabilitation programs in clinical practice.     

Oxidative DNA Damage in the Prostate May Predispose Men to a Higher Risk of Prostate Cancer

DNA damage has been associated with prostate cancer risk. Men who were referred for initial prostate biopsy for elevated prostate-specific antigen or abnormal digital rectal examination are often found with no cancer but have a higher risk of developing prostate cancer than the general population of men in their lifetime. In this study, we investigated whether DNA damage is one of the factors that predispose these men referred for prostate biopsies to a higher risk of prostate cancer. We found significantly elevated levels of 8-oxo-2-deoxyguanosine immunoreactivity in the prostates of the referred men (n = 50) in comparison to the control prostates of men (n = 32) with no indication for referral for prostate biopsy. Twelve of these control men were healthy middle-aged men and 20 of them were older men whose conditions were diagnosed with bladder cancer but with normal serum prostate-specific antigen and digital rectal examination and no evidence of prostate disease. In all the 8-oxo-2-deoxyguanosine-positive prostates, we detected phosphorylation of the ataxia telangiectasia mutated kinase and expression of the immune-stimulatory molecule MIC in the prostate epithelium. These data suggest that: 1) oxidative DNA damage has occurred in the “referred” but pathologically normal prostates, indicating that these prostates may be subjected to genomic instability and eventually neoplastic transformation; 2) in response to DNA damage, two surveillance pathways, represented by ataxia telangiectasia mutated phosphorylation and induction of the NKG2D ligand MIC, were activated to prevent tumorigenesis.     

Current state of practice regarding testosterone supplementation therapy in men with prostate cancer

Hypogonadal men are characterized by low serum testosterone and symptoms of low energy, decreased libido, and muscle mass as well as impaired concentration and sexual functioning. Men with prostate cancer (PCa) currently on active surveillance or post-therapy, have traditionally been excluded from management paradigms given the decade-old concern that testosterone caused PCa growth. However, there appears to be little or no relationship between serum testosterone concentration and PCa. Androgen action in the prostate has long been known to be affected by the kinetics of receptor saturation and, as such, testosterone beyond a certain baseline is unable to stimulate prostatic growth due to complete intra-prostatic androgen receptor binding. Given this physiologic concept, many clinical investigators have begun to promote testosterone supplementation therapy (TST) as safe in men with PCa. This review examines the basics of testosterone physiology and summarizes the most recent findings on the use of TST in men with PCa on active surveillance and following treatment with external beam radiotherapy, brachytherapy and radical prostatectomy.     

Spectral clustering for TRUS images

Background  

Identifying the location and the volume of the prostate is important for ultrasound-guided prostate brachytherapy. Prostate volume is also important for prostate cancer diagnosis. Manual outlining of the prostate border is able to determine the prostate volume accurately, however, it is time consuming and tedious. Therefore, a number of investigations have been devoted to designing algorithms that are suitable for segmenting the prostate boundary in ultrasound images. The most popular method is the deformable model (snakes), a method that involves designing an energy function and then optimizing this function. The snakes algorithm usually requires either an initial contour or some points on the prostate boundary to be estimated close enough to the original boundary which is considered a drawback to this powerful method.     

Pathological and molecular mechanisms of prostate carcinogenesis: implications for diagnosis, detection, prevention, and treatment

Prostate cancer is an increasing threat throughout the world. As a result of a demographic shift in population, the number of men at risk for developing prostate cancer is growing rapidly. For 2002, an estimated 189,000 prostate cancer cases were diagnosed in the U.S., accompanied by an estimated 30,200 prostate cancer deaths [Jemal et al., 2002]. Most prostate cancer is now diagnosed in men who were biopsied as a result of an elevated serum PSA (>4 ng/ml) level detected following routine screening. Autopsy studies [Breslow et al., 1977; Yatani et al., 1982; Sakr et al., 1993], and the recent results of the Prostate Cancer Prevention Trial (PCPT) [Thompson et al., 2003], a large scale clinical trial where all men entered the trial without an elevated PSA (<3 ng/ml) were subsequently biopsied, indicate the prevalence of histologic prostate cancer is much higher than anticipated by PSA screening. Environmental factors, such as diet and lifestyle, have long been recognized contributors to the development of prostate cancer. Recent studies of the molecular alterations in prostate cancer cells have begun to provide clues as to how prostate cancer may arise and progress. For example, while inflammation in the prostate has been suggested previously as a contributor to prostate cancer development [Gardner and Bennett, 1992; Platz, 1998; De Marzo et al., 1999; Nelson et al., 2003], research regarding the genetic and pathological aspects of prostate inflammation has only recently begun to receive attention. Here, we review the subject of inflammation and prostate cancer as part of a "chronic epithelial injury" hypothesis of prostate carcinogenesis, and the somatic genome and phenotypic changes characteristic of prostate cancer cells. We also present the implications of these changes for prostate cancer diagnosis, detection, prevention, and treatment.     

Zinc Intake and Risk of Prostate Cancer: Case-Control Study and Meta-Analysis

Zinc is an essential dietary element that has been implicated in the pathogenesis of prostate cancer, a cancer that disproportionately affects men of African descent. Studies assessing the association of zinc intake and prostate cancer have yielded inconsistent results. Furthermore, very little is known about the relationship between zinc intake and prostate cancer among African Americans. We examined the association between self-reported zinc intake and prostate cancer in a hospital-based case-control study of African Americans. We then compared our results with previous studies by performing a meta-analysis to summarize the evidence regarding the association between zinc and prostate cancer. Newly diagnosed African American men with histologically confirmed prostate cancer (n = 127) and controls (n = 81) were recruited from an urban academic urology clinic in Washington, DC. Controls had higher zinc intake, with a mean of 14 mg/day versus 11 mg/day for cases. We observed a non-significant, non-linear increase in prostate cancer when comparing tertiles of zinc intake (OR _{<6.5 vs 6.5–12.5mg/day} 1.8, 95% CI: 0.6,5.6; OR _{<6.5 vs >12.5mg/day} 1.3, 95% CI: 0.2,6.5). The pooled estimate from 17 studies (including 3 cohorts, 2 nested case-control, 11 case-control studies, and 1 randomized clinical trial, with a total of 111,199 participants and 11,689 cases of prostate cancer) was 1.07_{hi vs lo} 95% CI: 0.98–1.16. Using a dose-response meta-analysis, we observed a non-linear trend in the relationship between zinc intake and prostate cancer (p for nonlinearity = 0.0022). This is the first study to examine the relationship between zinc intake in black men and risk of prostate cancer and systematically evaluate available epidemiologic evidence about the magnitude of the relationship between zinc intake and prostate cancer. Despite of the lower intake of zinc by prostate cancer patients, our meta-analysis indicated that there is no evidence for an association between zinc intake and prostate cancer.     

Drug therapies for eradicating high-grade prostatic intraepithelial neoplasia in the prevention of prostate cancer

High-grade prostatic intraepithelial neoplasia (HGPIN) is a precursor to invasive prostate cancer observed as an isolated entity in a growing subset of men undergoing prostate biopsy. The presence of HGPIN predicts an increased risk of 1) coexisting occult prostate cancer at baseline and 2) delayed progression to prostate cancer. As such, men with HGPIN represent a population at high risk for the development of prostate cancer. Because the current recommended therapy is observation and delayed-interval biopsies until cancer develops, a well-tolerated therapeutic agent capable of interrupting the progression of HGPIN to cancer is highly desirable. Given the known cancer-stimulatory effects of estrogens in the prostate, the use of selective estrogen receptor modulators (SERMs) to provide an antiestrogen effect represents a novel strategy for prostate cancer prevention. Recent phase II data from trials using toremifene in the treatment of men with HGPIN validate the use of SERMs as a rational and provocative strategy for the prevention of prostate cancer.     

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.     

HPC2 variants and screen-detected prostate cancer

Two studies have reported significant associations between susceptibility to prostate cancer and two common missense variants of the HPC2/ELAC2 gene, with estimated relative risks in the range of two- to threefold. We investigated whether these polymorphisms could be informative in the prediction of the presence of prostate cancer in men undergoing prostatic biopsy for the evaluation of an elevated serum-PSA level (> or = 4.0 ng/ml). We genotyped 944 men who underwent a prostate biopsy at our institution, as well as a control population of 922 healthy, unselected women from the same population. The prevalence of the HPC2 Ala541Thr allele was similar in men with prostate cancer (6.3%), men with other prostatic conditions (6.8%), and healthy women (6.3%) (P = .83). We conclude that HPC2 genotyping is unlikely to be a useful adjunct to PSA in the prediction of the presence of biopsy-detected prostate cancer in asymptomatic men.