Prostatic irradiation-induced sexual dysfunction: a review and multidisciplinary guide to management in the radical radiotherapy era (Part I defining the organ at risk for sexual toxicities)

Prostate cancer is the most common malignancy 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. Erectile, ejaculatory and orgasm dysfunction(s) is/are known potential and common toxicities associated with prostate radiotherapy. Our multidisciplinary team of physicians and/or scientists have written a three (3) part comprehensive review of the pathogenesis and management radiation-induced sexual dysfunction. Part I reviews pertinent anatomy associated with normal sexual function and then considers the pathogenesis of prostate radiation-induced sexual toxicities. Next, our team considers the associated radiobiological (including the effects of time, dose and fractionation) and physical (treatment planning and defining a novel Organ at Risk (OAR)) components that should be minded in the context of safe radiation treatment planning. The authors identify an OAR (i.e., the prostatic plexus) and provide suggestions on how to minimize injury to said OAR during the radiation treatment planning process.     

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.     

Bladder Cancer After Radiotherapy for Prostate Cancer

External beam radiotherapy (EBRT) is frequently used in the management of prostate cancer (PCa) as definitive, postoperative, or salvage local treatment. Although EBRT plays a central role in the management of PCa, complications remain a troubling by-product. Several studies have demonstrated an association between radiotherapy and elevated risk of acute and late toxicities. A secondary malignancy induced by initial therapy represents one of the most serious complications related to definitive cancer treatment. The radiation-related secondary primary malignancy risk increases with increasing survival time. Transitional cell carcinoma of the bladder is the most frequent secondary primary malignancy occurring after radiotherapy and is described as more aggressive; it may be diagnosed later because some radiation oncologists believe that the hematuria that occurs after prostate EBRT is normal. Some patients treated for localized PCa will subsequently develop invasive bladder cancer requiring surgical intervention. Patients with PCa treated with EBRT should be monitored closely for the presence of bladder cancer.Key words: Bladder cancer, Prostate cancer, Radiotherapy, External beam radiotherapyThe phenomenon of radiation-inducing the carcinogenesis has been well described in literature for decades. The correlation between ionizing radiation and DNA damage has been discussed in several studies.^1–4 Most of these studies evaluated the growth of solid tumors in a large population exposed to moderate to heavy doses of radiation, such as factory workers, patients exposed to a large number of diagnostic radiographic studies, and survivors of atomic and nuclear explosions. ¹ The casual effects of radiation exposure with subsequent mutagenesis are quite clear, shown both in vivo and in vitro.² Previous radiotherapy (RT) for prostate cancer (PCa) may play an important role in the development of secondary primary bladder cancer. This is a fairly uncommon event but a very real entity, of which both urologists and radiation oncologists need to be aware.     

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.     

Epidermal Growth Factor Receptor in Prostate Cancer Derived Exosomes

Exosomes proteins and microRNAs have gained much attention as diagnostic tools and biomarker potential in various malignancies including prostate cancer (PCa). However, the role of exosomes and membrane-associated receptors, particularly epidermal growth factor receptor (EGFR) as mediators of cell proliferation and invasion in PCa progression remains unexplored. EGFR is frequently overexpressed and has been associated with aggressive forms of PCa. While PCa cells and tissues express EGFR, it is unknown whether exosomes derived from PCa cells or PCa patient serum contains EGFR. The aim of this study was to detect and characterize EGFR in exosomes derived from PCa cells, LNCaP xenograft and PCa patient serum. Exosomes were isolated from conditioned media of different PCa cell lines; LNCaP xenograft serum as well as patient plasma/serum by differential centrifugation and ultracentrifugation on a sucrose density gradient. Exosomes were confirmed by electron microscopy, expression of exosomal markers and NanoSight^™ analysis. EGFR expression was determined by western blot analysis and ELISA. This study demonstrates that exosomes may easily be derived from PCa cell lines, serum obtained from PCa xenograft bearing mice and clinical samples derived from PCa patients. Presence of exosomal EGFR in PCa patient exosomes may present a novel approach for measuring of the disease state. Our work will allow to build on this finding for future understanding of PCa exosomes and their potential role in PCa progression and as minimal invasive biomarkers for PCa.     

Estrogens and anti-estrogens: key mediators of prostate carcinogenesis and new therapeutic candidates

Despite the historical use of estrogens in the treatment of prostate cancer (PCa) little is known about their direct biological effects on the prostate, their role in carcinogenesis, and what mechanisms mediate their therapeutic effects on PCa. It is now known that estrogens alone, or in synergism with an androgen, are potent inducers of aberrant growth and neoplastic transformation in the prostate. The mechanisms of estrogen carcinogenicity could be mediated via induction of unscheduled cell proliferation or through metabolic activation of estrogens to genotoxic metabolites. Age-related changes and race-/ethnic-based differences in circulating or locally formed estrogens may explain differential PCa risk among different populations. Loss of expression of estrogen receptor (ER)-beta expression during prostate carcinogenesis and prevention of estrogen-mediated oxidative damage could be exploited in future PCa prevention strategies. Re-expression of ER-beta in metastatic PCa cells raises the possibility of using ER-beta-specific ligands in triggering cell death in these malignant cells. A variety of new estrogenic/anti-estrogenic/selective estrogen receptor modulator (SERM)-like compounds, including 2-methoxyestradiol, genistein, resveratrol, licochalcone, Raloxifene, ICI 182,780, and estramustine are being evaluated for their potential in the next generation of PCa therapies. Increasing numbers of patients self-medicate with herbal formulations such as PC-SPES. Some of these compounds are selective ER-beta ligands, while most of them have minimal interaction with ER-alpha. Although many may inhibit testosterone production by blockade of the hypothalamal-pituitary-testis axis, the most effective agents also exhibit direct cytostatic, cytotoxic, or apoptotic action on PCa cells. Some of them are potent in interfering with tubulin polymerization, blocking angiogenesis and cell motility, suppressing DNA synthesis, and inhibiting specific kinase activities. Further discovery of other compounds with potent apoptotic activities but minimal estrogen action should promote development of a new generation of effective PCa preventive or treatment regimens with few or no side-effects due to estrogenicity. Further advancement of our knowledge of the role of estrogens in prostate carcinogenesis through metabolic activation of estrogens and/or ER-mediated pathways will certainly result in better preventive or therapeutic modalities for PCa.     

The Case for Hypofractionation of Localized Prostate Cancer

An optimal treatment regimen for localized prostate cancer (PCa) is yet to be determined. Increasing evidence reveals a lower α/β ratio for PCa with hypofractionated radiation therapy (HFRT) regimens introduced to exploit this change in therapeutic ratio. HFRT also results in shortened overall treatment times of 4 to 5 weeks, thus reducing staffing and machine burden, and, more importantly, patient stress. This review evaluates pretreatment characteristics, outcomes, and toxicity for 15 HFRT studies on localized PCa. HFRT results in comparable or better biochemical relapse-free survival and toxicity and is a viable option for localized PCa.Key words: Localized prostate cancer, Hypofractionation, Short-course radiotherapy, Dose escalation, Biologic equivalenceMultiple randomized dose-escalation trials for localized prostate cancer (PCa) have shown improved biochemical relapse-free survival (bRFS) rates for higher total doses using conventionally fractionated radiotherapy (CFRT), though at a cost of longer treatment duration.^1–4 The increased treatment time requires increased access to radiation treatment facilities, with additional burden on both patients and staff. To address the issue of prolonged treatment duration while maintaining equivalent bRFS, an increasing number of studies have pursued the role of hypofractionated radiotherapy (HFRT) with higher daily doses delivered in a shorter total amount of time. This treatment paradigm assumes a low α/β ratio for PCa, as demonstrated in several recent studies, with higher α/β ratios for normal surrounding tissues.^5–7 By employing HFRT, the increased daily radiation doses exploit the aforementioned α/β ratios by allowing equivalent tumor kill as with CFRT, while also allowing for normal tissue repair.With longer-term and randomized HFRT data now reported in the literature, it seems appropriate to address whether the time has come to make HFRT the new standard. This article seeks to review the current literature and the role of HFRT in the modern era of radiotherapy for localized PCa.     

Sexual partners,sexually transmitted infections,and prostate cancer risk

Background: The etiology of prostate cancer (PCa) is poorly understood. Sexual activity and sexually transmitted infections (STIs) are among factors under scrutiny, with controversial findings to date. Methods: We examined the association between the number and gender of sexual partners, STIs and PCa risk in the context of PROtEuS, a population-based case–control study set amongst the mainly French-speaking population in Montreal, Canada. The study included 1590 histologically-confirmed PCa cases diagnosed in a Montreal French hospital between 2005 and 2009, and 1618 population controls ascertained from the French electoral list, Montreal residents, frequency-matched to cases by age. In-person interviews elicited information on sociodemographic, lifestyle and environmental factors. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) between sexually related factors and PCa risk, adjusting for age, ancestry, family history of PCa, and PCa screening history. Results: Subjects with more than 20 sexual partners in their lifetime had a decreased risk of PCa (OR 0.78, 95% CI 0.61–1.00) as did subjects who specifically had more than 20 female sexual partners (OR 0.72, 95% CI 0.56–0.94). By contrast, having had several male sexual partners appeared to confer some excess in risk of PCa. No association emerged for history of STIs and PCa but STIs prevalence was low. Conclusion: Our findings are in support of a role for the number of sexual partners in PCa development. The gender of sexual partners should be taken into account in future studies investigating this association.     

食管癌患者在放射治疗中不同营养途径的护理管理效应

目的:探讨不同营养途径包括直接经食管与间接经鼻饲、胃造瘘进食的食管癌患者在放射治疗过程中的护理措施和方法对患者的临床效应。方法:回顾性分析我科一年来放射治疗的63例食管鳞状细胞癌患者的临床资料,其中46例患者直接经食管进食,其余17例治疗前行鼻饲或胃造瘘进食,在治疗过程中注重对患者的心理护理、饮食及放疗并发症护理。结果:放疗前行鼻饲或食管造瘘患者在放疗过程中依从性好,放射性食管炎能更好的控制,未发生食管穿孔及食管气管瘘等重大放疗并发症。结论:放疗前行鼻饲或胃造瘘的食管癌患者,周密的观察与细致的护理,主动的护患沟通,会导致积极的临床效应,可减轻放射损伤,降低食管穿孔及食管气管瘘的几率,延长患者生命,提高其生活质量。     

The role of microRNAs in prostate cancer migration,invasion, and metastasis

Prostate cancer (PCa) is considered the most prevalent malignancy and the second major cause of cancer-related death in males from Western countries. PCa exhibits variable clinical pictures, ranging from dormant to highly metastatic cancer. PCa suffers from poor prognosis and diagnosis markers, and novel biomarkers are required to define disease stages and to design appropriate therapeutic approach by considering the possible genomic and epigenomic differences. MicroRNAs (miRNAs) comprise a class of small noncoding RNAs, which have remarkable functions in cell formation, differentiation, and cancer development and contribute in these processes through controlling the expressions of protein-coding genes by repressing translation or breaking down the messenger RNA in a sequence-specific method. miRNAs in cancer are able to reflect informative data about the current status of disease and this might benefit PCa prognosis and diagnosis since that is concerned to PCa patients and we intend to highlight it in this paper.     

Intensity modulated radiotherapy in carcinoma cervix with metastatic para-aortic nodes: an institutional experience from a Regional Cancer Centre of Eastern India

BackgroundCervical cancer is a major health problem, especially in developing countries like India. Extended field radiotherapy (EFRT) for cancer cervix treatment remains a challenging task for radiation oncologists. In the last decade studies have shown that EFRT using intensity modulated radiotherapy (IMRT) is feasible in treating gynaecological malignancies but there is a dearth of literature on this specific topic from this part of the world where patient profile differs greatly in several aspects from that of the western world. The aim of the study was evaluation of treatment response and toxicity profile in cases of carcinoma cervix with metastatic para-aortic nodes treated with intensity modulated radiotherapy technique.Materials and methodsIn this retrospective study the treatment records of 45 para-aortic node positive cervical cancer patients treated with EFRT (IMRT) and concurrent cisplatin were analysed for evaluation of loco-regional control and toxicities.ResultsForty-four patients received full course of treatment. Among those 44 patients, 93.2% achieved complete response. Overall, the treatment was tolerated well and toxicities were within acceptable limits. Acute grade 3–4 toxicities were observed mostly in the form of anaemia and leucopenia. Most common late toxicities were those of small and large intestine.ConclusionEFRT with concurrent chemotherapy was successfully delivered for para-aortic nodes positive cervical cancer patients in Indian scenario where under-nutrition, infection, anaemia and several other factors adversely influence treatment outcome. Pelvic and para-aortic control rates were satisfactory. The technique was associated with an acceptable acute and late toxicity profile.     

Inverse relationship between PSA and IL-8 in prostate cancer: an insight into a NF-κB-mediated mechanism

Background

Prostate specific antigen (PSA) is traditionally used as an indicator for the presence of prostate cancer (PCa) and radiotherapy is generally used to treat inoperable and locally advanced PCa. However, how cellular PSA level is associated with sensitivity of PCa to radiotherapy is unknown. The previous finding that the RelB-based NF-κB alternative pathway differentially regulates PSA and interleukin-8 (IL-8) in aggressive PCa has directed our attention to the role of RelB in the response of PCa to radiotherapy.

Methodology/Principal Findings

RelB and its targets PSA and IL-8 in PCa cells were manipulated by ectopic expression in PCa cells with a low endogenous level of RelB (LNCaP) and by RNAi-based knock-down in PCa cells with a high constitutive level of RelB (PC3). The effects of RelB, PSA and IL-8 on the response of PCa to radiation treatment were examined in vitro and in xenograft tumors. RelB regulates PSA and IL-8 in an inverse manner. When the cellular levels of PSA and IL-8 were directly modulated by genetic manipulations or by the addition of recombinant proteins, the results demonstrate that up-regulation of IL-8 enhanced radioresistance of PCa cells and concurrently down-regulated PSA. In contrast, up-regulation of PSA resulted in reduced radioresistance with concurrent down-regulation of IL-8.

Conclusion/Significance

RelB plays a critical role in the response of PCa to radiotherapy and the inverse expression of IL-8 and PSA. The results identify a previously unrecognized relationship between IL-8 and PSA in the response of PCa cells to radiotherapy.     

Androgen deprivation therapy in combination with radiotherapy for high-risk clinically localized prostate cancer

Androgen deprivation therapy (ADT) has remained the main therapeutic option for patients with advanced prostate cancer (PCa) for about 70 years. Several reports and our findings revealed that aggressive PCa can occur under a low dihydrotestosterone (DHT) level environment where the PCa of a low malignancy with high DHT dependency cannot easily occur. Low DHT levels in the prostate with aggressive PCa are probably sufficient to propagate the growth of the tumor, and the prostate with aggressive PCa can produce androgens from the adrenal precursors more autonomously than that with non-aggressive PCa does under the low testosterone environment with testicular suppression. In patients treated with ADT the pituitary-adrenal axis mediated by adrenocorticotropic hormone has a central role in the regulation of androgen synthesis. Several experimental studies have confirmed the potential benefits from the combination of ADT with radiotherapy (RT). A combination of external RT with short-term ADT is recommended based on the results of phase III randomized trials. In contrast, the combination of RT plus 6 months of ADT provides inferior survival as compared with RT plus 3 years of ADT in the treatment of locally advanced PCa. Notably, randomized trials included patients with diverse risk groups treated with older RT modalities, a variety of ADT scheduling and duration and, importantly, suboptimal RT doses. The use of ADT with higher doses of RT or newer RT modalities has to be properly assessed.     

Green tea polyphenols for prostate cancer chemoprevention: A translational perspective

Every year nearly 200,000 men in the United States are diagnosed with prostate cancer (PCa), and another 29,000 men succumb to the disease. Within certain regions of the world population based studies have identified a possible role for green tea in the prevention of certain cancers, especially PCa. One constituent in particular, epigallocatechin-3-gallate also known as EGCG has been shown in cell culture models to decrease cell viability and promote apoptosis in multiple cancer cell lines including PCa with no effect on non-cancerous cell lines. In addition, animal models have consistently shown that standardized green tea polyphenols when administered in drinking water delay the development and progression of PCa. Altogether, three clinical trials have been performed in PCa patients and suggest that green tea may have a distinct role as a chemopreventive agent. This review will present the available data for standardized green tea polyphenols in regard to PCa chemoprevention that will include epidemiological, mechanism based studies, safety, pharmacokinetics, and applicable clinical trials. The data that has been collected so far suggests that green tea may be a promising agent for PCa chemoprevention and further clinical trials of participants at risk of PCa or early stage PCa are warranted.     

CCR2 expression correlates with prostate cancer progression

Although the primary role of chemokines and their receptors is controlling the trafficking of leukocytes during inflammatory responses, they also play pleoitropic roles in cancer development. There is emerging evidence that cancer cells produce chemokines that induce tumor cell proliferation or chemotaxis in various cancer types. We have previously reported that MCP-1 acts as a paracrine and autocrine factor for prostate cancer (PCa) growth and invasion. As the cellular effects of MCP-1 are mediated by CC chemokine receptor 2 (CCR2), we hypothesized that CCR2 may contribute PCa progression. Accordingly, we first determined CCR2 mRNA and protein expression in various cancer cell lines, including PCa and other cancer types. All cells expressed CCR2 mRNA and protein, but in PCa, more aggressive cancer cells such as C4-2B, DU145, and PC3 expressed a higher amount of CCR2 compared with the less aggressive cancer cells such as LNCaP or non-neoplastic PrEC and RWPE-1 cells. Further, we found a positive correlation between CCR2 expression and PCa progression by analyzing an ONCOMINE gene array database. We confirmed that CCR2 mRNA was highly expressed in PCa metastatic tissues compared with the localized PCa or benign prostate tissues by real-time RT-PCR. Finally, CCR2 protein expression was examined by immunohistochemical staining on tissue microarray specimens from 96 PCa patients and 31 benign tissue controls. We found that CCR2 expression correlated with Gleason score and clinical pathologic stages, whereas lower levels of CCR2 were expressed in normal prostate tissues. These results suggest that CCR2 may contribute to PCa development.     

Impact of 68Ga-PSMA PET/CT in the treatment of prostate cancer: Initial experience in Spain

AimTo evaluate whether positron-emission tomography/computed tomography with ⁶⁸Ga-PSMA (⁶⁸Ga-PSMA PET/CT) influences the therapeutic management of patients with primary or recurrent prostate cancer (PCa).BackgroundAlthough ⁶⁸Ga-PSMA PET/CT is one of the best options for staging or restaging patients with PCa, its availability is still very limited in Spain. The present study reports the results of the first group of patients in Spain who underwent ⁶⁸Ga-PSMA PET/CT imaging.Materials and methodsAll patients (n = 27) with a histological diagnosis of PCa who underwent ⁶⁸Ga-PSMA PET/CT prior to the definitive treatment decision at the only centre with this technology in Spain during 2017–2018 were included. Two nuclear medicine physicians and a radiologist reviewed the imaging studies. The clinical impact was assessed from a theoretical perspective, based on the treatment that would have been applied if no data from the ⁶⁸Ga-PSMA PET/CT were available.ResultsMost patients (n = 26; 96%) had persistent disease or biochemical recurrence after radical prostatectomy, radiotherapy, or combined treatment. One patient underwent ⁶⁸Ga-PSMA PET/CT imaging to stage high-risk PCa. Overall, ⁶⁸Ga-PSMA PET/CT was positive in 19 patients (70.4%). In 68.75% of these patients, none of the other imaging tests—MRI, CT, or bone scans—performed prior to the ⁶⁸Ga-PSMA PET/CT were able to detect the presence of cancerous lesions. Overall, the findings of the ⁶⁸Ga-PSMA PET/CT led to a modification of the therapeutic approach in 62.96% of the patients in the study.Conclusions⁶⁸Ga-PSMA PET/CT alters the therapeutic approach in a substantial proportion of patients with PCa.     

Tissue Proteome Signatures Associated with Five Grades of Prostate Cancer and Benign Prostatic Hyperplasia

The histology‐based Gleason score (GS) of prostate cancer (PCa) tissue biopsy is the most accurate predictor of disease aggressiveness and an important measure to guide treatment strategies and patient management. The variability associated with PCa tumor sampling and the subjective determination of the GS are challenges that limit accurate diagnostication and prognostication. Thus, novel molecular signatures are needed to distinguish between indolent and aggressive forms of PCa for better patient management and outcomes. Herein, label‐free LC‐MS/MS proteomics is used to profile the proteome of 50 PCa tissues spanning five grade groups (n = 10 per group) relative to tissues from individuals with benign prostatic hyperplasia (BPH). Over 2000 proteins are identified albeit at different levels between and within the patient groups, revealing biological processes associated with specific grades. A panel of 11 prostate‐derived proteins including IGKV3D‐20, RNASET2, TACC2, ANXA7, LMOD1, PRCP, GYG1, NDUFV1, H1FX, APOBEC3C, and CTSZ display the potential to stratify patients from low and high PCa grade groups. Parallel reaction monitoring of the same sample cohort validate the differential expression of LMOD1, GYG1, IGKV3D‐20, and RNASET2. The four proteins associated with low and high PCa grades reported here warrant further exploration as candidate biomarkers for PCa aggressiveness.     

Improving outcomes in high-risk prostate cancer with radiotherapy

There have been significant improvements in the radiotherapeutic management of patients with high risk prostate cancer. Randomized trials have clearly demonstrated improved outcomes with the combination of radiotherapy in conjunction with androgen deprivation. While these trials have utilized low doses of radiotherapy in the range of 70 Gy, recent studies have suggested that significant benefits of combined androgen deprivation therapy with dose escalated radiotherapy are also observed. The use of high radiation dose levels in the setting of high risk prostate cancer is important, and strategies which combine external beam radiotherapy with a brachytherapy boost may provide an opportunity for even greater intensification of the radiation dose to the prostate target. Systemic therapies, second generation anti-androgen therapy and novel targeted agents integrated with radiotherapy will open up new vistas and challenges for further improved outcomes in patients with high-risk disease.