Focal Laser Ablation of Prostate Cancer: Numerical Simulation of Temperature and Damage Distribution

Background

The use of minimally invasive ablative techniques in the management of patients with low grade and localized prostate tumours could represent a treatment option between active surveillance and radical therapy. Focal laser ablation (FLA) could be one of these treatment modalities. Dosimetry planning and conformation of the treated area to the tumor remain major issues, especially when, several fibers are required. An effective method to perform pre-treatment planning of this therapy is computer simulation. In this study we present an in vivo validation of a mathematical model.

Methods

The simulation model is based on finite elements method (FEM) to solve the bio-heat and the thermal damage equations. Laser irradiation was performed with a 980 nm laser diode system (5 W, 75 s). Light was transmitted using a cylindrical diffusing fiber inserted inside a preclinical animal prostate cancer model induced in Copenhagen rats. Non-enhanced T2-weighted and dynamic gadolinium-enhanced T1-weighted MR imaging examinations were performed at baseline and 48 hours after the procedure. The model was validated by comparing the simulated necrosis volume to the results obtained in vivo on (MRI) and by histological analysis. 3 iso-damage temperatures were considered 43° C, 45° C and 50° C.

Results

The mean volume of the tissue necrosis, estimated from the histological analyses was 0.974 ± 0.059 cc and 0.98 ± 0.052 cc on the 48 h MR images. For the simulation model, volumes were: 1.38 cc when T = 43° C, 1.1 cc for T = 45°C and 0.99 cc when T = 50 C°.

Conclusions

In this study, a clear correlation was established between simulation and in vivo experiments of FLA for prostate cancer.Simulation is a promising planning technique for this therapy. It needs further more evaluation to allow to FLA to become a widely applied surgical method.

     

Proton Beam Therapy for Localized Prostate Cancer 101: Basics,Controversies, and Facts

Proton beam therapy for prostate cancer has become a source of controversy in the urologic community, and the rapid dissemination and marketing of this technology has led to many patients inquiring about this therapy. Yet the complexity of the technology, the cost, and the conflicting messages in the literature have left many urologists ill equipped to counsel their patients regarding this option. This article reviews the basic science of the proton beam, examines the reasons for both the hype and the controversy surrounding this therapy, and, most importantly, examines the literature so that every urologist is able to comfortably discuss this option with inquiring patients.Key words: Prostate cancer, Proton beam therapy, External beam radiation therapy, Intensity modulated radiation therapyProton beam therapy (PBT) has become a source of controversy in the urologic community. It is not uncommon to hear mixed messages regarding the issue, from zealous advocates to cost-conscious skeptics, leaving many urologists unsure what to tell their patients with prostate cancer. What is clear, however, is that the technology is disseminating across the nation, and as our patients turn to the internet to learn more about their diagnosis, they are going to encounter increasingly more information about PBT, both scientific and promotional in nature. Hence, it is necessary for every urologist to understand the basics of PBT to help guide our patients through treatment options. This article reviews and compares the basic science of conventional external beam radiation therapy (EBRT) with PBT, examines the reasons for both the hype and the controversy surrounding this therapy, and, most importantly, examines the literature so that all urologists are adequately equipped to counsel their patients on this subject.     

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.     

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.     

Screening for Prostate Cancer: A Review of the ERSPC and PLCO Trials

The advent of prostate-specific antigen (PSA) testing in the early 1980s revolutionized the diagnosis of prostate cancer. As a result of PSA testing, there has been a surge in the number of prostate cancer diagnoses. This review examines the results of 2 recent landmark trials that studied the effect of screening on prostate cancer mortality: the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US-based Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.Key words: PSA screening, European Randomized Study of Screening for Prostate Cancer (ERSPC), Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening TrialProstate cancer poses a significant problem for men’s health; it has become the most common malignancy and the second most common cause of cancer death in American men. It is estimated that 1 in 6 men will be diagnosed with prostate cancer at some time in their lives, and more than 30,000 men died of the disease in 2002.¹ The advent of prostate-specific antigen (PSA) testing in the early 1980s revolutionized the diagnosis of prostate cancer, and, as a result, there has been a surge in the number of prostate cancer diagnoses.Similar to other common malignancies, such as breast and cervical cancer, population screening with this effective tumor marker appears enticing, and the American health care model has advocated PSA screening since the early 1990s. This review examines the results of 2 recent landmark trials: the European Randomized Study of Screening for Prostate Cancer (ERSPC)¹ and the US-based Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.² The results of these trials have contributed significantly to our understanding of the effects and efficacy of prostate cancer screening, and its difficulties. Both trials examined mortality as the endpoint, and both found little effect on mortality from screening.     

Focal Therapy: A New Paradigm for the Treatment of Prostate Cancer

Focal therapy has been proposed in recent years as a means of bridging the gap between radical prostatectomy and active surveillance for treatment of prostate cancer. The rationale for focal therapy comes from its success in treating other malignancies. One of the challenges in applying such an approach to the treatment of prostate cancer has been the multifocal nature of the disease. This review addresses the selection of potentially ideal candidates for focal therapy and discusses which modalities are currently being used and proposed for focal therapy. Setting and meeting guidelines for oncologic efficacy is a challenge we must embrace to safely deliver this potentially revolutionary approach to treating men with prostate cancer.Key words: Focal therapy, Photodynamic therapy, Prostatic neoplasms, Prostate-specific antigen, Prostatectomy, Ultrasound, high-intensity focused, transrectal, CryosurgeryWith the advent of prostate-specific antigen (PSA) screening there has been a stage migration, with radical prostatectomy (RP) being performed with increasing frequency in men with low-risk disease.¹ Whole gland treatment of prostate cancer carries a significant risk of incontinence and sexual dysfunction. Even in the most experienced centers, the rate of potency following RP is approximately 60%.^2–4 Stage migration has led many to recommend active surveillance (AS) as a means to decrease the number of men who may be overtreated; however, AS has been slow to gain acceptance in the United States.An analysis of over 5300 men from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) National Prostate Cancer Registry⁵ showed that only 7% of men with clinically localized prostate cancer chose AS as an initial option. Aside from the anxiety that stems from not treating a diagnosed cancer, the greater difficulty with AS lies in selection of candidates and appropriate parameters for surveillance, allowing prompt intervention without compromising cure rates.Focal therapy has been proposed in recent years as a means of bridging the gap between whole gland treatment and AS. Many believe that for patients with low-risk disease, focal therapy is the ideal option for maximizing quality of life by avoiding the effects of whole gland radiation or surgery while alleviating the anxiety and uncertainty of AS. The definition of focal therapy itself is not well established and includes lesion-targeted therapy (LAT), hemiablative therapy (HAT), or subtotal gland therapy (STAT), sparing at least 1 neurovascular bundle.⁶The rationale for focal therapy comes from its success in treating other malignancies. In breast cancer treatment, for example, radical mastectomy has been replaced in many instances by local excision and Mohs surgery has led to less radical surgery for the treatment of melanoma.⁷ In our own field, the push for nephron-sparing surgery has led to the favoring of partial nephrectomy in tumors less than 7 cm, with oncologic outcomes similar to those of radical nephrectomy.⁸The challenge in applying such an approach to the treatment of prostate cancer has been the multifocal nature of prostate cancer and the fact that most cancers are detected without identifying a lesion on palpation or imaging studies.^9,10In this review, we revisit the current status of focal therapy in the treatment of prostate cancer. We discuss whether there are ideal candidates for focal therapy; we then discuss how these candidates should be selected. We review which modalities are currently being used and proposed for focal therapy. Finally, we discuss potential definitions of successful treatment. As this article shows, there are still many aspects of focal therapy that are yet to be defined, that warrant a great need for further research.     

Widespread and Functional RNA Circularization in Localized Prostate Cancer

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Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Prostate Cancer Clinical Trials: Potential Roles and Possible Pitfalls

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) evaluates the tissue microvasculature and may have a role in assessing and predicting therapeutic response in prostate cancer (PCa). In this review, we review principles of DCE-MRI and present the potential quantitative information that can be obtained. We discuss how it may be used as a biomarker for treatment with antiangiogenic and antivascular agents and potentially identify patients with PCa who may benefit from this form of therapy. Likewise, DCE-MRI may play a role in assessing response to combined androgen deprivation therapy and radiation therapy and theoretically could be a prognostic biomarker in evaluating second-generation hormone therapies. We also address the challenges of using DCE-MRI in PCa clinical trials and discuss the difficulties with standardization of this methodology to allow for biomarker validation, with particular reference to PCa.     

Therapeutic Strategies for Localized Prostate Cancer II: Perineal Prostatectomy, X-Rays, Protons, Neutrons, and Combination Brachytherapy

Application of improved imaging, diagnostic, and computer techniques is beginning to have an impact on the management of localized prostate cancer. It is possible to perform a range of surgical and radiation procedures with less morbidity than in the past. The changes in therapy for patients with localized disease derive from better knowledge of anatomy for invasive procedures and optimization of virtual planning for noninvasive methods. Perineal prostatectomy and combinations of beam and seed radiation offer both patient and physician reasonable therapeutic options.     

Randomization to Screening for Prostate,Lung, Colorectal and Ovarian Cancers and Thyroid Cancer Incidence in Two Large Cancer Screening Trials

Background

Thyroid cancer incidence has increased significantly over the past three decades due, in part, to incidental detection. We examined the association between randomization to screening for lung, prostate, colorectal and/or ovarian cancers and thyroid cancer incidence in two large prospective randomized screening trials.

Methods

We assessed the association between randomization to low-dose helical CT scan versus chest x-ray for lung cancer screening and risk of thyroid cancer in the National Lung Screening Trial (NLST). In the Prostate Lung Colorectal and Ovarian Cancer Screening Trial (PLCO), we assessed the association between randomization to regular screening for said cancers versus usual medical care and thyroid cancer risk. Over a median 6 and 11 years of follow-up in NLST and PLCO, respectively, we identified 60 incident and 234 incident thyroid cancer cases. Cox proportional hazards regression was used to calculate the cause specific hazard ratios (HR) and 95% confidence intervals (CI) for thyroid cancer.

Results

In NLST, randomization to lung CT scan was associated with a non-significant increase in thyroid cancer risk (HR  = 1.61; 95% CI: 0.96–2.71). This association was stronger during the first 3 years of follow-up, during which participants were actively screened (HR  = 2.19; 95% CI: 1.07–4.47), but not subsequently (HR  = 1.08; 95% CI: 0.49–2.37). In PLCO, randomization to cancer screening compared with usual care was associated with a significant decrease in thyroid cancer risk for men (HR  = 0.61; 95% CI: 0.49–0.95) but not women (HR  = 0.91; 95% CI: 0.66–1.26). Similar results were observed when restricting to papillary thyroid cancer in both NLST and PLCO.

Conclusion

Our study suggests that certain medical encounters, such as those using low-dose helical CT scan for lung cancer screening, may increase the detection of incidental thyroid cancer.     

抗肿瘤抗体-药物偶联物的临床研究进展

个体化靶向治疗已成为肿瘤临床治疗的新趋势.抗肿瘤靶向药物与传统的细胞毒性化疗药物相比具有特异性高、选择性强和非细胞毒性等优点,近年来发展迅速.抗体-药物偶联物(ADCs)属于抗肿瘤靶向药物,由抗体、“弹头”药物(细胞毒性药物)通过链分子连接而成.ADCs将抗体的靶向性与细胞毒性药物的抗肿瘤作用相结合,可以降低细胞毒性抗肿瘤药物的不良反应,提高肿瘤治疗的选择性,还能更好地应对靶向单抗的耐药性问题.目前,FDA已批准2种ADC药物上市,即Mylotarg和Adcetris,有多种ADCs处于Ⅰ～Ⅲ期临床试验阶段,取得了显著的临床效果.本文概述了以美登素,卡奇霉素、Auristantin等三种细胞毒性药物为“弹头”药物的ADCs药物的临床研究状况及临床试验结果,为ADCs的研究和应用提供参考.     

Short-Term Soy Isoflavone Intervention in Patients with Localized Prostate Cancer: A Randomized,Double-Blind,Placebo-Controlled Trial

Purpose

We describe the effects of soy isoflavone consumption on prostate specific antigen (PSA), hormone levels, total cholesterol, and apoptosis in men with localized prostate cancer.

Methodology/Principal Findings

We conducted a double-blinded, randomized, placebo-controlled trial to examine the effect of soy isoflavone capsules (80 mg/d of total isoflavones, 51 mg/d aglucon units) on serum and tissue biomarkers in patients with localized prostate cancer. Eighty-six men were randomized to treatment with isoflavones (n = 42) or placebo (n = 44) for up to six weeks prior to scheduled prostatectomy. We performed microarray analysis using a targeted cell cycle regulation and apoptosis gene chip (GEArrayTM). Changes in serum total testosterone, free testosterone, total estrogen, estradiol, PSA, and total cholesterol were analyzed at baseline, mid-point, and at the time of radical prostatectomy. In this preliminary analysis, 12 genes involved in cell cycle control and 9 genes involved in apoptosis were down-regulated in the treatment tumor tissues versus the placebo control. Changes in serum total testosterone, free testosterone, total estrogen, estradiol, PSA, and total cholesterol in the isoflavone-treated group compared to men receiving placebo were not statistically significant.

Conclusions/Significance

These data suggest that short-term intake of soy isoflavones did not affect serum hormone levels, total cholesterol, or PSA.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00255125","term_id":"NCT00255125"}}NCT00255125     

前列腺钙化灶的超声显像诊断与分型的临床研究

目的：探究超声显像诊断前列腺钙化灶（PFC）的临床实用价值和超声分型。方法：对1284倒经腹部超声显像诊断为PFC的临床资料进行回顾性分析,并根据超声所见进行分型。结果：超声显像诊断PFC1,284例,单发768倒（59．81％）。多发516例（40．19％）;钙化灶直径2-36mm;Ⅰ度542例（42．21％）,Ⅱ度460例（35．83％）,Ⅲ度282例（21．96％）;孤立型412例（32．09％）,散在型319例（24．84％）,聚集型395例（30．76％）,条索型158例（12-31％）。内腺435例（33．88％）、外腺348例（（27．10％）、内外腺交界处351例（27．34％）、后尿道周围150例（11．68％）。单纯性钙化520例（40．50％）,合并前列腺增生597例（46．50％）、前列腺炎129例（10．05％）、前列腺囊肿36例（2．80％）、前列腺癌2例（0．16％）。结论：PFC是男性泌尿生殖系统常见疾病,其程度和类型与年龄密切相关,近半数与前列腺增生并存,可能与组织退变、增生、炎症、钙磷代谢紊乱等因素有关。超声显像是诊断PFC最可靠、最简便的方法,具有重要的l陆床实用价值。     

前列腺钙化灶的超声显像诊断与分型的临床研究

目的:探究超声显像诊断前列腺钙化灶(PFC)的临床实用价值和超声分型。方法:对1284例经腹部超声显像诊断为PFC的临床资料进行回顾性分析,并根据超声所见进行分型。结果:超声显像诊断PFC 1,284例,单发768例(59.81%),多发516例(40.19%);钙化灶直径2~36mm;Ⅰ度542例(42.21%),Ⅱ度460例(35.83%),Ⅲ度282例(21.96%);孤立型412例(32.09%),散在型319例(24.84%),聚集型395例(30.76%),条索型158例(12.31%)。内腺435例(33.88%)、外腺348例((27.10%)、内外腺交界处351例(27.34%)、后尿道周围150例(11.68%)。单纯性钙化520例(40.50%),合并前列腺增生597例(46.50%)、前列腺炎129例(10.05%)、前列腺囊肿36例(2.80%)、前列腺癌2例(0.16%)。结论:PFC是男性泌尿生殖系统常见疾病,其程度和类型与年龄密切相关,近半数与前列腺增生并存,可能与组织退变、增生、炎症、钙磷代谢紊乱等因素有关。超声显像是诊断PFC最可靠、最简便的方法,具有重要的临床实用价值。     

Novel Pharmacologic Targeting of Tight Junctions and Focal Adhesions in Prostate Cancer Cells

Cancer cell resistance to anoikis driven by aberrant signaling sustained by the tumor microenvironment confers high invasive potential and therapeutic resistance. We recently generated a novel lead quinazoline-based Doxazosin® derivative, DZ-50, which impairs tumor growth and metastasis via anoikis. Genome-wide analysis in the human prostate cancer cell line DU-145 identified primary downregulated targets of DZ-50, including genes involved in focal adhesion integrity (fibronectin, integrin-α6 and talin), tight junction formation (claudin-11) as well as insulin growth factor binding protein 3 (IGFBP-3) and the angiogenesis modulator thrombospondin 1 (TSP-1). Confocal microscopy demonstrated structural disruption of both focal adhesions and tight junctions by the downregulation of these gene targets, resulting in decreased cell survival, migration and adhesion to extracellular matrix (ECM) components in two androgen-independent human prostate cancer cell lines, PC-3 and DU-145. Stabilization of cell-ECM interactions by overexpression of talin-1 and/or exposing cells to a fibronectin-rich environment mitigated the effect of DZ-50. Loss of expression of the intracellular focal adhesion signaling effectors talin-1 and integrin linked kinase (ILK) sensitized human prostate cancer to anoikis. Our findings suggest that DZ-50 exerts its antitumor effect by targeting the key functional intercellular interactions, focal adhesions and tight junctions, supporting the therapeutic significance of this agent for the treatment of advanced prostate cancer.     

Co-Occurring Gland Angularity in Localized Subgraphs: Predicting Biochemical Recurrence in Intermediate-Risk Prostate Cancer Patients

Quantitative histomorphometry (QH) refers to the application of advanced computational image analysis to reproducibly describe disease appearance on digitized histopathology images. QH thus could serve as an important complementary tool for pathologists in interrogating and interpreting cancer morphology and malignancy. In the US, annually, over 60,000 prostate cancer patients undergo radical prostatectomy treatment. Around 10,000 of these men experience biochemical recurrence within 5 years of surgery, a marker for local or distant disease recurrence. The ability to predict the risk of biochemical recurrence soon after surgery could allow for adjuvant therapies to be prescribed as necessary to improve long term treatment outcomes. The underlying hypothesis with our approach, co-occurring gland angularity (CGA), is that in benign or less aggressive prostate cancer, gland orientations within local neighborhoods are similar to each other but are more chaotically arranged in aggressive disease. By modeling the extent of the disorder, we can differentiate surgically removed prostate tissue sections from (a) benign and malignant regions and (b) more and less aggressive prostate cancer. For a cohort of 40 intermediate-risk (mostly Gleason sum 7) surgically cured prostate cancer patients where half suffered biochemical recurrence, the CGA features were able to predict biochemical recurrence with 73% accuracy. Additionally, for 80 regions of interest chosen from the 40 studies, corresponding to both normal and cancerous cases, the CGA features yielded a 99% accuracy. CGAs were shown to be statistically signicantly () better at predicting BCR compared to state-of-the-art QH methods and postoperative prostate cancer nomograms.