Focal Treatment of Prostate Cancer with Vascular-Targeted Photodynamic Therapy

Epidemiologic and pathologic features of prostate cancer have given rise to an interest in focal treatment for carefully selected patients. Prostate cancer remains highly prevalent, particularly in the U.S. and Europe. As screening programs have become more aggressive and widespread, a substantial proportion of men diagnosed with localized prostate cancer have disease characteristics associated with a low risk of progression. Treatments such as radical prostatectomy and radiation therapy can lead to durable recurrence-free survival in most patients, but carry variable risks of bowel, urinary, and sexual side effects. Few men and few urologists are comfortable leaving a potentially curable prostate cancer untreated. Focal therapy offers an attractive alternative for the patient faced with a choice between aggressive local intervention (radiation or surgery) and watchful waiting. Contemporary diagnostic biopsy strategies and imaging tools, and the development of predictive statistical models (nomograms), have led to improvements in tumor characterization and risk stratification, making focal therapy a viable treatment option for specific men. This article reviews the rationale and indications for focal therapy and highlights vascular-targeted photodynamic therapy (PDT) as one of many promising focal therapy techniques

Cathepsins B and D drive hepatic stellate cell proliferation and promote their fibrogenic potential

El pdf del artículo es el manuscrito de autor.-- PubMed: PMCID:PMC2670444Cathepsins have been best characterized in tumorigenesis and cell death and implicated in liver fibrosis; however, whether cathepsins directly regulate hepatic stellate cell (HSC) activation and proliferation, hence modulating their fibrogenic potential, is largely unknown. Here, we show that expression of cathepsin B (CtsB) and cathepsin D (CtsD) is negligible in quiescent HSCs but parallels the increase of -smooth muscle actin and transforming growth factor- during in vitro mouse HSC activation. Both cathepsins are necessary for HSC transdifferentiation into myofibroblasts, because their silencing or inhibition decreasedHSC proliferation and the expression of phenotypicmarkers ofHSC activation, with similar results observed with the human HSC cell line LX2. CtsB inhibition blunted AKT phosphorylation in activated HSCs in response to platelet-derived growth factor.Moreover, during in vivo liver fibrogenesis caused by CCl4 administration, CtsB expression increased in HSCs but not in hepatocytes, and its inactivation mitigated CCl4-induced inflammation, HSC activation, and collagen deposition. Conclusion: These findings support a critical role for cathepsins inHSC activation, suggesting that the antagonismof cathepsins inHSCsmay be of relevance for the treatment of liver fibrosis.Financial support: The work was supported by CIBEREHD and grant PI070193 (Instituto de Salud Carlos III); by grant SAF2006-06780 (Plan Nacional de I+D), Spain; and by grant P50-AA-11999 (Research Center for Liver and Pancreatic Diseases, US National Institute on Alcohol Abuse and Alcoholism).Peer reviewe

Role of genetic testing for inherited prostate cancer risk: Philadelphia prostate cancer consensus conference 2017

Purpose: Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-dri

Genomic Predictors of Outcome in Prostate Cancer

CONTEXT: Given the highly variable behavior and clinical course of prostate cancer (PCa) and the multiple available treatment options, a personalized approach to oncologic risk stratification is important. Novel genetic approaches offer additional information to improve clinical decision making. OBJECTIVE: To review the use of genomic biomarkers in the prognostication of PCa outcome and prediction of therapeutic response. EVIDENCE ACQUISITION: Systematic literature review focused on human clinical studies reporting outcome measures with external validation. The literature search included all Medline, Embase, and Scopus articles from inception through July 2014. EVIDENCE SYNTHESIS: An improved understanding of the genetic basis of prostate carcinogenesis has produced an increasing number of potential prognostic and predictive tools, such as transmembrane protease, serine2:v-ets avian erythroblastosis virus E26 oncogene homolog (TMPRSS2:ERG) gene fusion status, loss of the phosphatase and tensin homolog (PTEN) gene, and gene expression signatures utilizing messenger RNA from tumor tissue. Several commercially available gene panels with external validation are now available, although most have yet to be widely used. The most studied commercially available gene panels, Prolaris, Oncotype DX Genomic Prostate Score, and Decipher, may be used to estimate disease outcome in addition to clinical parameters or clinical nomograms. ConfirmMDx is an epigenetic test used to predict the results of repeat prostate biopsy after an initial negative biopsy. Additional future strategies include using genetic information from circulating tumor cells in the peripheral blood to guide treatment decisions at the initial diagnosis and at subsequent decision points. CONCLUSIONS: Major advances have been made in our understanding of PCa biology in recent years. Our field is currently exploring the early stages of a personalized approach to augment traditional clinical decision making using commercially available genomic tools. A more comprehensive appreciation of value, limitations, and cost is important. PATIENT SUMMARY: We summarized current advances in genomic testing in prostate cancer with a special focus on the estimation of disease outcome. Several commercial tests are currently available, but further understanding is needed to appreciate the potential benefits and limitations of these novel tests

Focal Treatment of Prostate Cancer with Vascular-Targeted Photodynamic Therapy

Epidemiologic and pathologic features of prostate cancer have given rise to an interest in focal treatment for carefully selected patients. Prostate cancer remains highly prevalent, particularly in the U.S. and Europe. As screening programs have become more aggressive and widespread, a substantial proportion of men diagnosed with localized prostate cancer have disease characteristics associated with a low risk of progression. Treatments such as radical prostatectomy and radiation therapy can lead to durable recurrence-free survival in most patients, but carry variable risks of bowel, urinary, and sexual side effects. Few men and few urologists are comfortable leaving a potentially curable prostate cancer untreated. Focal therapy offers an attractive alternative for the patient faced with a choice between aggressive local intervention (radiation or surgery) and watchful waiting. Contemporary diagnostic biopsy strategies and imaging tools, and the development of predictive statistical models (nomograms), have led to improvements in tumor characterization and risk stratification, making focal therapy a viable treatment option for specific men. This article reviews the rationale and indications for focal therapy and highlights vascular-targeted photodynamic therapy (PDT) as one of many promising focal therapy techniques. KEYWORDS: prostate cancer, focal therapy, photodynamic therapy WORLDWIDE HEALTH PROBLEM Prostate cancer continues to be a frequent cause of morbidity and death throughout the world. Despite the formidable prevalence of prostate cancer, no consensus exists regarding the merits of screening, selection of patients for primary treatment, and optimal treatment modality. The impact of disease and treatmentrelated morbidity has wide-ranging public health implications, particularly in countries where screening is common and male life expectancies are increasing. In 2004, an estimated 68,000 men in the European Union died of prostate cancer, making it the third most common cause of cancer-related death 964 PROSTATE CANCER DETECTION Prostate specific antigen (PSA) testing was approved in 1986 by the U.S. Food and Drug Administration to monitor men with prostate cancer. By the time PSA testing was formally approved for cancer detection in 1994, PSA screening had already become widespread, effectively ushering in the contemporary era of prostate cancer detection. Consequently, the age-adjusted incidence of prostate cancer has changed dramatically over the past several decades, rising from less than 92 cases/100,000 men in 1975 to a peak of 240 cases/100,000 men in 1992, before declining to a relatively constant level of 180 cases/100,000 men since 2001[4]. Since 1994, annual age-adjusted mortality rates in the U.S. have also steadily decreased, probably but not certainly as a result of early detection and effective therapy of potentially lethal early-stage cancers. Despite the shift toward improved prostate cancer detection and early diagnosis seen in the last 2 decades, the absence of an equally large impact on prostate cancer mortality has led some to question the benefits of PSA screening strategies. For example, in the U.S., the estimated ratio of incidence to mortality in 2006 was 8.6 [5]. In contrast, PSA screening has not been widely embraced in Europe. The lower incidence-to-mortality ratio in Europe (e.g., approximately 3.0 in the U.K.) suggests a comparatively lower rate of early diagnosis The discrepancy in incidence to mortality is likely due, in part, to increased detection of slowgrowing or relatively indolent prostate tumors among highly screened patients. Indeed, there is evidence to support a relatively high prevalence of indolent tumors that pose little immediate risk to health and life. Autopsy studies have shown high rates of incidental, localized, moderately differentiated, prostate cancer in men who died from other causes. Prostate cancer has been identified in 25-30% of these men Despite the geographic variations in prostate cancer screening, and the purported benefit of screening on early detection and disease-specific survival, the weight of these observations suggests that most men diagnosed with low-volume, moderately differentiated, prostate cancer will not succumb to this disease during their lifetime. The public health, individual, and financial implications are profound. It is admittedly difficult to predict with certainty an individual patient's long-term risk based on currently available pretreatment variables and trends of increasing life expectancy. However, by any metric, a substantial population of men is overdiagnosed and overtreated. THE TREATMENT OF PROSTATE CANCER AND ITS IMPLICATIONS At the time of diagnosis of a low-risk prostate cancer, a man may choose active therapy or watchful waiting, more recently referred to as active surveillance. For many men, foregoing treatment initially is an acceptable alternative. In avoiding the morbidity of treatment, they accept the rare but real possibility that the cancer will progress and become less curable at a later time. An active surveillance program attempts to minimize this risk by requiring scheduled office visits with repeat biopsy sessions at predetermined intervals or when clinically indicated. Active treatment may be recommended when there is evidence to suggest disease progression. Many criteria have been advanced as a threshold for intervention, but none have been validated as effective. Patient anxiety associated with these programs leads many to abandon this strategy despite a favorable clinical course, and, conversely, a small but meaningful number of men later found to have high-risk disease may be ill served by delaying treatment In the U.S., the health care community generally recommends active treatment with curative intent for healthy men with localized prostate cancer CHARACTERISTICS OF LOCALIZED PROSTATE CANCER Unifocal vs. Multifocal Prostate cancer has been shown to be multifocal. Even when the cancer is multifocal, most nonindex tumors appear to be biologically indolent based on their small size and low grade. Rukstalis et al. analyzed 112 whole-mount prostatectomy specimens and found 20% to have a unifocal cancer Predicting Biologic Indolence Numerous studies have retrospectively sought to identify patients with indolent cancer based on pretreatment parameters. Cheng et al. found the highest percentage of cancer at any biopsy site and the total number of positive biopsy sites to predict the likelihood of small-volume cancer (<0.5 cc) on final pathologic evaluation Epstein et al. used PSA density and pathologic findings on biopsy to predict insignificant cancers (defined as tumor volume <0.2 cm 3 , Gleason <7, and confined to the prostate) with 73% accuracy Kattan et al. incorporated PSA, clinical stage, prostate volume, Gleason score, total length of cancer on biopsy, and total length of noncancer on biopsy to construct a nomogram predicting indolent cancer (defined as <0.5 cm 3 , moderately differentiated with no Gleason component of 4 or 5, and confined to the prostate) with excellent discriminatory ability and calibration PRETREATMENT CANCER CHARACTERIZATION Magnetic Resonance Imaging (MRI) In order to identify candidates for focal therapy properly and confidently, it is imperative to have a reliable means for localizing and accurately delineating the tumor. Imaging would ideally provide an acceptable Eggener and Coleman: Focal Photodynamic Treatment of Prostate Cancer TheScientificWorldJOURNAL (2008) 8, 963-973 966 standard by which prostate cancers could be identified and characterized. In addition to patient selection, accurate imaging modalities would prove useful in directing therapy, assessing results, and monitoring for disease recurrence or progression. The ability to assess locoregional lymph nodes adequately to evaluate for metastatic spread is also needed. Among currently utilized prostate imaging modalities (ultrasound, computed tomography, and MRI), endorectal MRI with spectroscopy (MRSI) appears to offer the best operating characteristics and enhances the predictive accuracy of standard nomograms. The combination of endorectal MRI/MRSI and a clinicopathologic nomogram, when compared to the nomogram alone, adds substantially to the area under the receiver operating characteristic (ROC) curve (AUC) for predicting organ-confined cancer MRI can also assist in the estimation of tumor volume. In a study by Coakley et al.[21], the accuracy of MRI and MRSI in the measurement of prostate cancer tumor volume was assessed in 37 patients prior to radical prostatectomy. For peripheral zone tumor nodules >0.5 cm 3 , tumor volume measurements by MRI, MRSI, and combined MRI/MRSI were all positively correlated with histopathologic findings, but only measurements by MRSI and combined MRI/MRSI reached statistical significance. These results show that the combination of MRSI and MRI increases the overall accuracy of tumor volume measurement for lesions of this size, although measurement variability may limit consistent quantitative estimation in smaller tumors. While MRI augments standard clinical and pathologic parameters in predicting advanced disease features and tumor volume, it is unable to visualize reliably the small and well-differentiated cancers that may be the prime candidates for either active surveillance or focal therapy. When it occasionally does highlight the area of a small, unifocal tumor, image-guided focal ablation may confidently target that region. However, the clinical utility of MRI rests as much, if not more, on what it does not show. Imaging that suggests the absence of a cancer that is large, poorly differentiated, or has pathologically advanced features increases support for the diagnosis of a small cancer with little risk. Additionally, the intended role of MRI would be to guide focal ablative therapy more precisely since it provides a very detailed view of the normal prostate overall and can help target the proper region 967 Biopsy Characterization Strategies Prostate biopsies have evolved from finger-directed to ultrasound-guided, usually with injection of an anesthetic and commonly sampling a larger portion of the prostate. Current approaches call for 10-12 biopsy cores to be taken, resulting in increased detection of tumors RATIONALE FOR FOCAL THERAPY Historically, definitive treatment of solid cancers included whole-gland extirpation with radical surgery. For many organ systems, outcome data have supported more selective, organ-sparing, or even ablative therapies, such as breast-conservation surgery and less extensive surgery for melanoma Similar trends have been witnessed in urologic oncology. Historically, the standard treatment for all solid renal masses was radical nephrectomy. Within the past decade, cancer control following partial nephrectomy has been shown to be equivalent for tumors <4 cm, with the benefit of preserving renal function Prostate cancer may be amenable to organ-sparing, focal treatment. The prostate is a small, easily accessible organ, and many urologists are familiar with performing image-guided procedures in the gland through the rectum, perineum, or urethra. Intuitively, treatment would be required solely at the area of tumor, limiting collateral damage to normal tissue. While the potential of such therapies makes them attractive, the ramifications of treatment failure bear considerable forethought in the development of focal treatment trials. The issues of patient selection, appropriate targeting of lesions, and the impact of focal treatments on outcome with salvage surgical or radiation treatment all deserve consideration. Criteria for follow-up and patient evaluation, as well as indications for repeat treatment, also remain to be standardized. The role for focal therapy in the treatment of prostate cancer may be most applicable to patients with tumors that pose little risk of progression, as long as the treatment has minimal effect on quality of life and does not adversely impact survival. Focal ablation of the index cancer, or of the sector of the prostate that harbors that cancer, could be very attractive for patients with low-risk cancers who are uncomfortable with the risks associated with active surveillance and the side effects of radical therapy. The unanswered questions are whether appropriate candidates can be identified, whether the index cancer can be reliably characterized while excluding higher-grade secondary tumors, and whether focal ablation can reliably target and destroy the index cancer with few complications and side effects. Even with effective treatment, such patients will have to be followed closely after focal therapy, since they may be at high risk Eggener and Coleman: Focal Photodynamic Treatment of Prostate Cancer TheScientificWorldJOURNAL (2008) 8, 963-973 968 for developing another cancer in the prostate. Ultimately, the benefits of focal therapy will need to be proven with a randomized clinical trial comparing focal ablation to active surveillance or radical therapy. With these considerations in mind, a patient best suited for focal therapy would have a well-localized, targetable tumor of relatively small volume with a low-to-intermediate risk of metastatic spread and compliant with follow-up including repeat prostate biopsy procedures. Treatment must reliably eradicate tumors, have a low rate of side effects, and not complicate management with other therapies that may become necessary. One option for focal treatment that appears to meet several of these criteria is photodynamic therapy, which involves athermic treatment with relative sparing of tissue outside of the treatment field. PHOTODYNAMIC THERAPY Background Photodynamic therapy (PDT) is an ablative therapy that depends on three elements: a photosensitizer, light, and oxygen. The photosensitizer is typically given systemically by intravenous infusion and is present in the tissue of interest by perfusion of that organ. The photosensitizer is activated at the intended site of action, typically by fiberoptic illumination at a wavelength matched to the properties of the drug. In tissues, lesion size is dependent on a variety of factors, including tissue vascularity, drug concentration, and light intensity and duration. Through an unknown mechanism, photosensitizers preferentially accumulate in regions of proliferating cells, allowing PDT to display some selectivity for targeting a tumor while minimizing damage to surrounding normal tissue. The light-sensitive photosensitizing agent, which may be administered either topically or intravenously, is activated by a specific wavelength of light energy and creates oxygen-dependent cytotoxic and vasculotoxic reactions Current PDT techniques primarily target the cellular compartment to destroy a tumor, but newer vascular-targeting photosensitizers (verteporfin, WST09) are activated while in the vasculature. This property can be exploited to cause vascular damage (occlusion, perforation, and stasis), enhancing tissue necrosis and allowing improved penetration of cytotoxic agents Given the ease of photosensitizer application, PDT is most frequently used on cutaneous lesions, but has also been tested on breast, central nervous system, head and neck, lung, esophageal, cervical, bladder, and prostate cancers. When used as prostate cancer therapy, advantages of PDT include minimally invasive access via the perineum, with techniques similar to brachytherapy Preclinical Studies WST09 is one of the latest PDT agents developed through the Weizmann Institute in Israel. WST09 is a chlorophyll-derived photosensitizer with several desirable properties, including rapid intravascular clearance Eggener and Coleman: Focal Photodynamic Treatment of Prostate Cancer TheScientificWorldJOURNAL (2008) 8, 963-973 and minimal tissue accumulation, decreasing the risks of photosensitivity. Its absorption wavelength at 763 nm is within the near infrared range, allowing reasonable tissue penetration using fiberoptic light application. Preclinical studies in animal models have demonstrated its safety profile and antitumor effect. 969 Initial investigations in both canine and murine models identified the safety and treatment parameters for WST09-PDT treatment. Intravenous drug infusion to a dose concentration between 2 and 4 mg/kg was well tolerated. Fiberoptic-delivered interstitial illumination with a diode laser at lambda = 770 nm was Eggener and Coleman: Focal Photodynamic Treatment of Prostate Cancer TheScientificWorldJOURNAL (2008) 8, 963-973 970 capable of creating lesions of hemorrhagic necrosis as large as 3 cm in the canine prostate gland Photosensitivity studies were performed in both animals and humans to evaluate any cutaneous reaction to incident full-spectrum light exposure. Drug dosing at 2 mg/kg and skin exposure to both UVand UV+ solar-simulated light at 128 J/cm 2 did not demonstrate skin photosensitivity at exposure durations up to 3 h. Drug doses >2 mg/kg were associated with evidence of phototoxicity in the murine and porcine models, and were not administered to human subjects Damage to tissue structures outside of the prostate gland are possible with PDT therapy and are likely when illumination outside of the boundaries of the prostate occurs. Evaluation of tissue sensitivities to WST09-PDT was performed in the canine model. Nerve conduction studies immediately and 1 week following treatment to the cutaneous branch of the saphenous nerve revealed light dose-dependent functional damage when light exposure over 100 J/cm 2 was used. Exposure at 50 J/cm 2 showed minimal conduction effects WST09-PDT Technique A feasibility study of PDT in humans has been completed. In a Phase I trial of 24 patients with radiorecurrent prostate cancer, dose escalation of WST09 up to 2 mg/kg and light doses up to 360 J/cm were generally well tolerated Using general anesthesia, the patient was positioned in the lithotomy position with an ultrasound probe in the rectum and a brachytherapy template applied to the perineum. A catheter was inserted into each lobe of the prostate via the template and visualized via the transrectal probe. Optical fibers set at 763 nm for light delivery and probes to detect light dosimetry and temperature were placed within the catheters. Additional probes were placed within a translucent urethral catheter and the anterior rectum to monitor light exposure to these areas. To minimize rectal exposure to light, a hydrodissection procedure on the plane between the rectum and prostate was performed. Following infusion of WST09, escalating doses and duration of light were administered. No signs of treatment response were seen at a drug dose <1.0 mg/kg, leading investigators to define these patients as nonresponders in the trial. In addition to safety data collected as part of this Phase I trial, tissue end points were also evaluated by interval radiographic imaging and prostate biopsy. At 7 days following treatment, hypoperfusion was noted on MRI at the maximum drug and light doses. Biopsies performed 6 months after treatment showed fibrosis and no evidence of viable cancer in areas found to be avascular on post-treatment MRI in men with response. However, small islands of benign tissue were seen, possibly indicating a selective effect of the treatment on tumor-bearing tissue. Treatment effects were not evident on biopsies from untreated regions. PSA declined to negligible levels in four of the six patients who received the maximum light and photosensitizer dose. Evidence of transient hepatic enzyme increase was seen in a subset of patients without sequelae. All patients voided spontaneously following 7-14 days of catheterization. A significant decline in urinary function was noted in five patients who demonstrated treatment response, defined by a prostate necrosis volume ≥20% on MRI 7 days post-PDT. The mean change in International Prostate Symptom Score (IPSS) score at 1 month following treatment was 20 points with gradual improvement resulting over the subsequent 5 months. Bowel and erectile function were not significantly affected, as measured by the Patient-Oriented Prostate Utility Scale (PORPUS) 971 Mature data from this trial and others are required to assess the potential role of PDT in treating localized prostate cancer following radiation therapy. Given the encouraging safety profile and evidence of a treatment effect, a Phase II trial of 24 patients in a similar clinical setting has begun. Of the 16 patients with ≥6 month follow-up in the Phase II trial, hypoperfused MRI lesions and decreases in PSA have been noted. Given the results of these preliminary trials, PDT is also actively being investigated for primary treatment of low-risk, localized prostate cancer

Active surveillance monitoring: the role of novel biomarkers and imaging

"CANCER" is a disease state that leads to progressive illness that is uniformly fatal without treatment. Hippocrates invoked the Greek word karkinos, or "crab," to describe tumors he observed. For centuries, "CANCER" remained a disease that was recognized primarily in its locally advanced or metastatic stage, when it was almost uniformly fatal

Management of good-risk metastatic nonseminomatous germ cell tumors of the testis: Current concepts and controversies

Introduction/Methods : Approximately 30% of nonseminomatous germ-cell tumors (NSGCT) of the testis present with metastatic disease. In 1997, the International Germ Cell Cancer Collaborative Group (IGCCCG) stratified all patients with metastatic NSGCT into various risk groups based on serum tumor markers and presence of visceral disease. We review the literature and present optimal stage-dependent management strategies in patients with favorable-risk metastatic NSGCT. Results : Primary chemotherapy (3 cycles BEP or 4 cycles EP) has been shown to be the preferred modality in patients with Clinical Stage IS (cIS) and in patients with bulky metastatic disease (≥CS IIb) due to their high risk of systemic disease and recurrence. Primary retroperitoneal lymph node dissection appears to be the most efficient primary therapy for retroperitoneal disease 5 nodes involved, single node > 2 cm) and for those who are non-compliant with surveillance regimens. Following primary chemotherapy, STM and radiographic evaluation are used to assess treatment response. For patients with normalization of STM and retroperitoneal masses 1 cm and extra-retroperitoneal masses should be treated with surgical resection, which should be performed with nerve-sparing, if possible. Conclusions : In patients with favorable disease based on IGCCCG criteria, clinical stage, STM, and radiographic evaluation are used to guide appropriate therapy to provide excellent long-term cure rates (>92%) in patients with metastatic NSGCT