Focal Therapy For Prostate Cancer Research Articles

MP52-19 AGE STRATIFIED PROPENSITY SCORE MATCHED STUDY OUTCOMES OF ROBOTIC ASSISTED RADICAL PROSTATECTOMY

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2014MP52-19 AGE STRATIFIED PROPENSITY SCORE MATCHED STUDY OUTCOMES OF ROBOTIC ASSISTED RADICAL PROSTATECTOMY Srinivas Samavedi, Haidar Abdul-Muhsin, Suneel Pigilam, Kenneth Palmer, George Ebra, Ananthakrishnan Sivaraman, Vipul Patel, and Rafael Coelho Srinivas SamavediSrinivas Samavedi More articles by this author , Haidar Abdul-MuhsinHaidar Abdul-Muhsin More articles by this author , Suneel PigilamSuneel Pigilam More articles by this author , Kenneth PalmerKenneth Palmer More articles by this author , George EbraGeorge Ebra More articles by this author , Ananthakrishnan SivaramanAnanthakrishnan Sivaraman More articles by this author , Vipul PatelVipul Patel More articles by this author , and Rafael CoelhoRafael Coelho More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1629AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives Elderly patients have the potential of increased morbidity from prostate surgery. Our goal was to evaluate the perioperative and short term oncological outcomes of RARP in patients above 70 years. Methods The study population (N=3241) consisted of consecutive patients who underwent RARP for localized prostate cancer by a single surgeon (VP) from January 2008 through February 2012. Patients who received prior radiation, focal therapy for prostate cancer, androgen deprivation therapy or classified as salvage were excluded from the study. A query of our Institutional Review Board approved registry identified 400 men 70 years of age and over who were computer-matched in a 1:1 ratio to younger patients using an optimal matching algorithm. Perioperative and postoperative functional and oncologic outcomes for the two groups were compared Results The study groups demonstrated no significant differences in preoperative clinical characteristics except age. The mean operative time was significantly less for younger patients 75.9 min vs 78.9 min (p<0.005). The estimated blood loss and transfusion rate was similar. Full nerve sparing as well as the ease of nerve sparing were also similar. Intraoperative complications were comparable. Postoperative pathological examination were equivalent in the occurrence of positive surgical margins, pathological stage T, Gleason sum score, seminal vesicle invasion, extracapsular extension, tumor volume and dimension. Prostate weight was higher for elderly patients 62.5 g vs 54.3 g (p<0.001). Postoperative complication occurrence rates were similar (93.3% vs 93.5%). Pain scores, hospital length of stay and indwelling catheter days were comparable. At follow-up, younger patients had a continence rate of 94.1% vs older patients 90.4%. average time to continence was similar (3.0 months in younger men vs 3.2 months in older men) and for potency 6.5 months for younger patients vs. 5.7 months for older patients. A greater proportion of younger patients became potent than elderly (p<0.001). At 60 months, freedom from biochemical recurrence(BCR) ± standard error of the mean for younger patients was 89.4% ± 2.1 (17 patients at risk) and 89.4% ± 2.1 (20 patients at risk) for the older group. The mean time to BCR for younger patients (n=33) was 14.5 months ± 12.3 and 18.7 months ± 13.5 for older patients (n=31) Conclusions Patients above 70 years of age have no increased perioperative morbidity inferior oncological outcomes compared to younger patients. In appropriately selected patients prostatectomy is a resonable option © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e587 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Srinivas Samavedi More articles by this author Haidar Abdul-Muhsin More articles by this author Suneel Pigilam More articles by this author Kenneth Palmer More articles by this author George Ebra More articles by this author Ananthakrishnan Sivaraman More articles by this author Vipul Patel More articles by this author Rafael Coelho More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Drug and Device Development for Localized Prostate Cancer: Report of a Food and Drug Administration/American Urological Association Public Workshop

Summary of the discussion at a public workshop cosponsored by the U.S. Food and Drug Administration (FDA) and the American Urological Association reviewing potential trial designs for product and device development for the treatment of localized prostate cancer. Product development for treatment of localized prostate cancer has been stymied by the impracticality of using overall survival as an endpoint in patients with localized disease and the lack of acceptable surrogate endpoints. A workshop evaluating potential trial designs for the development of therapies for localized prostate cancer was held in San Diego, CA, in May 2013. Invited experts represented multiple stakeholders, including urology, medical oncology, radiation oncology, industry, and patient advocates. The expert panel discussed development of products for all risk strata of clinically localized prostate cancer. The panel responded to specific questions from FDA, discussing trial design for patients with low-, intermediate-, and high-risk prostate cancer, focal therapy for prostate cancer, patients who have undergone definitive radiation therapy, and adjuvant therapy for patients undergoing radiation therapy or surgery. Expert commentary provided by the panel will inform a planned FDA guidance on pathways for product and device development for treatment of localized prostate cancer and will be discussed at meetings of the FDA's Oncologic Drugs Advisory Committee. FDA intends to develop a set of principles that can be used to promote the development of new products or devices for the treatment of this disease.

A consensus on trial design for focal therapy

Focal therapy of prostate cancer enables treatment of the index lesion while sparing the rest of the gland and surrounding vital structures, thereby decreasing the risk of morbidity. As clinicians acknowledge its potential, the recently published multidisciplinary consensus is timely and provides new insight into trial design for focal therapy.

Focal Therapy in Prostate Cancer: International Multidisciplinary Consensus on Trial Design

BackgroundFocal therapy has been introduced for the treatment of localised prostate cancer (PCa). To provide the necessary data for consistent assessment, all focal therapy trials should be performed according to uniform, systematic pre- and post-treatment evaluation with well-defined end points and strict inclusion and exclusion criteria. ObjectiveTo obtain consensus on trial design for focal therapy in PCa. Design, setting, and participantsA four-staged consensus project based on a modified Delphi process was conducted in which 48 experts in focal therapy of PCa participated. According to this formal consensus-building method, participants were asked to fill out an iterative sequence of questionnaires to collect data on trial design. Subsequently, a consensus meeting was held in which 13 panellists discussed acquired data, clarified the results, and defined the conclusions. Outcome measurements and statistical analysisA multidisciplinary board from oncologic centres worldwide reached consensus on patient selection, pretreatment assessment, evaluation of outcome, and follow-up. Results and limitationsInclusion criteria for candidates in focal therapy trials are patients with prostate-specific antigen <15 ng/ml, clinical stage T1c–T2a, Gleason score 3+3 or 3+4, life expectancy of >10 yr, and any prostate volume. The optimal biopsy strategy includes transrectal ultrasound-guided biopsies to be taken between 6 mo and 12 mo after treatment. The primary objective should be focal ablation of clinically significant disease with negative biopsies at 12 mo after treatment as the primary end point. ConclusionsThis consensus report provides a standard for designing a feasible focal therapy trial. Patient summaryA variety of ablative technologies have been introduced and applied in a focal manner for the treatment of prostate cancer (PCa). In this consensus report, an international panel of experts in the field of PCa determined pre- and post-treatment work-up for focal therapy research.

Focal Therapy in Prostate Cancer: International Multidisciplinary Consensus on Trial Design

Focal Therapy in Prostate Cancer: International Multidisciplinary Consensus on Trial Design

Low temperature plasma: a novel focal therapy for localized prostate cancer?

Despite considerable advances in recent years for the focal treatment of localized prostate cancer, high recurrence rates and detrimental side effects are still a cause for concern. In this review, we compare current focal therapies to a potentially novel approach for the treatment of early onset prostate cancer: low temperature plasma. The rapidly evolving plasma technology has the potential to deliver a wide range of promising medical applications via the delivery of plasma-induced reactive oxygen and nitrogen species. Studies assessing the effect of low temperature plasma on cell lines and xenografts have demonstrated DNA damage leading to apoptosis and reduction in cell viability. However, there have been no studies on prostate cancer, which is an obvious candidate for this novel therapy. We present here the potential of low temperature plasma as a focal therapy for prostate cancer.

Multiparametric MRI in biopsy guidance for prostate cancer: fusion-guided.

Prostate cancer (PCa) is the most common solid-organ malignancy among American men and the second most deadly. Current guidelines recommend a 12-core systematic biopsy following the finding of an elevated serum prostate-specific antigen (PSA). However, this strategy fails to detect an unacceptably high percentage of clinically significant cancers, leading researchers to develop new, innovative methods to improve the effectiveness of prostate biopsies. Multiparametric-MRI (MP-MRI) has emerged as a promising instrument in identifying suspicious regions within the prostate that require special attention on subsequent biopsy. Fusion platforms, which incorporate the MP-MRI into the biopsy itself and provide active targets within real-time imaging, have shown encouraging results in improving the detection rate of significant cancer. Broader applications of this technology, including MRI-guided focal therapy for prostate cancer, are in early phase trials.

Tumor Target Volume for Focal Therapy of Prostate Cancer—Does Multiparametric Magnetic Resonance Imaging Allow for a Reliable Estimation?

We determined whether endorectal multiparametric magnetic resonance imaging at 1.5 Tesla could predict tumor target volume in the perspective of focal therapy of prostate cancer. A total of 84 consecutive patients underwent multiparametric magnetic resonance imaging before radical prostatectomy. The volume of each suspicious area detected on magnetic resonance imaging and of all surgical histological foci was determined by planimetry. We first used each magnetic resonance imaging sequence (T2-weighted, diffusion weighted and dynamic contrast enhanced) and then the sequence showing the largest tumor area (multiparametric volume). Finally, the largest area of any sequence was used to calculate a target volume according to the volume of a cylinder. Agreement between magnetic resonance imaging and pathological findings was assessed by linear regression and residual analysis. Histology revealed 99 significant tumors with a volume of greater than 0.2 cc and/or a Gleason score of greater than 6. Of the tumors 16 (16.2%) were undetected by multiparametric magnetic resonance imaging. Linear regression analysis showed that tumor volume estimated by T2-weighted or diffusion weighted imaging correlated significantly with pathological volume (r(2) = 0.82 and 0.83, respectively). Residuals from diffusion weighted imaging volume estimations did not significantly differ from 0. Nevertheless, diffusion weighted imaging underestimated pathological volume in 43 of 87 cases (49%) by a mean of 0.56 cc (range 0.005 to 2.84). Multiparametric and target volumes significantly overestimated pathological volume by a mean of 16% and 44% with underestimation in 28 (32%) and 15 cases (17%), respectively. Volume underestimation was significantly higher for tumor foci less than 0.5 cc. The percent of Gleason grade 4 did not influence tumor volume estimation. Magnetic resonance imaging can detect most significant tumors. However, delineating a target volume may require further adjustment before planning magnetic resonance imaging targeted focal treatment.

The role of magnetic resonance imaging (MRI) in focal therapy for prostate cancer: recommendations from a consensus panel

To establish a consensus on the utility of multiparametric magnetic resonance imaging (mpMRI) to identify patients for focal therapy. Urological surgeons, radiologists, and basic researchers, from Europe and North America participated in a consensus meeting about the use of mpMRI in focal therapy of prostate cancer. The consensus process was face-to-face and specific clinical issues were raised and discussed with agreement sought when possible. All participants are listed among the authors. Topics specifically did not include staging of prostate cancer, but rather identifying the optimal requirements for performing MRI, and the current status of optimally performed mpMRI to (i) determine focality of prostate cancer (e.g. localising small target lesions of ≥0.5 mL), (ii) to monitor and assess the outcome of focal ablation therapies, and (iii) to identify the diagnostic advantages of new MRI methods. In addition, the need for transperineal template saturation biopsies in selecting patients for focal therapy was discussed, if a high quality mpMRI is available. In other words, can mpMRI replace the role of transperineal saturation biopsies in patient selection for focal therapy? Consensus was reached on most key aspects of the meeting; however, on definition of the optimal requirements for mpMRI, there was one dissenting voice. mpMRI is the optimum approach to achieve the objectives needed for focal therapy, if made on a high quality machine (3T with/without endorectal coil or 1.5T with endorectal coil) and judged by an experienced radiologist. Structured and standardised reporting of prostate MRI is paramount. State of the art mpMRI is capable of localising small tumours for focal therapy. State of the art mpMRI is the technique of choice for follow-up of focal ablation. The present evidence for MRI in focal therapy is limited. mpMRI is not accurate enough to consistently grade tumour aggressiveness. Template-guided saturation biopsies are no longer necessary when a high quality state of the art mpMRI is available; however, suspicious lesions should always be confirmed by (targeted) biopsy.

Editorial Comment to Denonvilliers' space expansion by transperineal injection of hydrogel: Implications for focal therapy of prostate cancer

Editorial Comment to Denonvilliers' space expansion by transperineal injection of hydrogel: Implications for focal therapy of prostate cancer

Denonvilliers' space expansion by transperineal injection of hydrogel: Implications for focal therapy of prostate cancer

We developed and assessed a technique of: (i) expanding Denonvilliers' space by hydrogel (polyethylene glycol) during focal cryoabation; and (ii) temperature mapping to ensure protection of the rectal wall. In a fresh cadaver, 20 cc of hydrogel was injected transperineally into Denonvilliers' space under transrectal ultrasound guidance. Successful expansion of Denonvilliers' space was achieved with a range of 9-11 mm thickness covering the entire posterior prostate surface. Two freeze-thaw cycles were used to expand the iceball reaching the rectal wall as an end-point. Intraoperative transrectal ultrasound monitoring and temperature mapping in Denonvilliers' space by multiple thermocouples documented real-time iceball expansion up to 10 mm beyond the prostate, and safety in protecting the rectal wall from thermal injury. The lowest temperatures of the thermocouples with a distance of 0 mm, 5 mm and 10 mm from the prostate were: -35°C, -18°C and 0°C (P < 0.001), respectively. In gross and microscopic examination, the hydrogel mass measured 11 × 40 × 34 mm, which was identical to the intraoperative transrectal ultrasound measurements, there was no infiltration of the hydrogel into the rectal wall or prostate and no injury to the pelvic organs. In conclusion, the expansion of Denonvilliers' space by transperineal injection of hydrogel is feasible and a promising technique to facilitate energy-based focal therapy of prostate cancer.

Focal Therapy and Prostate Cancer

The International Task Force on Prostate Cancer defines focal therapy (FT) for prostate cancer (PCa) as the therapy that "selectively ablates known disease and preserves existing functions, with the overall objective of minimizing lifetime morbidity without compromising life expectancy". FT for the treatment of PCa has been called the "male lumpectomy", an analogue to women's breast lumpectomy for the treatment of breast cancer. Radical prostatectomy continues to be the most frequently performed treatment for localized PCa, as anatomic knowledge and several technical advances, i.e. the introduction of robotic assisted surgery, have led to successful oncological outcome and lower rates of post-treatment morbidity. However, a proportion of patients still experiences a no negligible sexual, urinary, and bowel morbidity. Although the rationale of active surveillance for low-risk PCa (PSA <10 ng/mL, Gleason grade 6 or less, and clinical stage T1c-T2a) is sound, only few of newly diagnosed patients elect this approach. Thus, in the recent years the concept of a "subtotal therapy" gained the interest of some urological schools. The aim of this paper is to review the existing literature in order to provide the status of art on FT for PCa. The manuscript will focus on the characteristics of the target population, on the pre-operative evaluation to localise disease, as well as on perioperative, functional, and disease-control following focal therapy.

Considerations for patient selection for focal therapy

Focal therapy for prostate cancer is a nascent and emerging field. As such, the patient selection criteria for this new treatment paradigm are evolving in parallel to both the technology on which this approach depends and to our unfolding understanding of the natural history of prostate cancer. Until, and while, prospective trials of focal therapy are being reported, patient selection criteria will be flexible and very dependent on the therapeutic goals. We must carefully define the therapeutic intentions of focal therapy before engaging in the actual process of determining optimal patient selection. The therapeutic intent will define the most appropriate candidate for such therapy. Patient selection encompasses multiple complex issues including the type of prostate biopsy (12 core transrectal versus mapping transperineal) to the type of imaging (multiparametric magnetic resonance imaging or enhanced ultrasound) to the specific anatomical location of the disease within the prostate (apex, mid-prostate, base) and a comprehensive assessment of the patient's overall health and life expectancy. It is not as simple as saying a patient with a certain grade or a certain number of cores is or is not appropriate for focal therapy. There are many more considerations for a reasonable and thoughtful approach to this new treatment.

Image‐directed, tissue‐preserving focal therapy of prostate cancer: a feasibility study of a novel deformable magnetic resonance‐ultrasound (MR‐US) registration system

ObjectiveTo evaluate the feasibility of using computer-assisted, deformable image registration software to enable three-dimensional (3D), multi-parametric (mp) magnetic resonance imaging (MRI)-derived information on tumour location and extent, to inform the planning and conduct of focal high-intensity focused ultrasound (HIFU) therapy.Patients and MethodsA nested pilot study of 26 consecutive men with a visible discrete focus on mpMRI, correlating with positive histology on transperineal template mapping biopsy, who underwent focal HIFU (Sonablate 500®) within a prospective, Ethics Committee-approved multicentre trial (‘INDEX’).Non-rigid image registration software developed in our institution was used to transfer data on the location and limits of the index lesion as defined by mpMRI.Manual contouring of the prostate capsule and histologically confirmed MR-visible lesion was performed preoperatively by a urologist and uro-radiologist.A deformable patient-specific computer model, which captures the location of the target lesion, was automatically generated for each patient and registered to a 3D transrectal ultrasonography (US) volume using a small number (10–20) of manually defined capsule points.During the focal HIFU, the urologist could add additional sonications after image-registration if it was felt that the original treatment plan did not cover the lesion sufficiently with a margin.ResultsProstate capsule and lesion contouring was achieved in <5 min preoperatively. The mean (range) time taken to register images was 6 (3–16) min.Additional treatment sonications were added in 13 of 26 cases leading to a mean (range) additional treatment time of 45 (9–90) s.ConclusionNon-rigid MR-US registration is feasible, efficient and can locate lesions on US.The process has potential for improved accuracy of focal treatments, and improved diagnostic sampling strategies for prostate cancer.Further work on whether deformable MR-US registration impacts on efficacy is required.

Focal Therapy for Prostate Cancer: Rationale and Treatment Opportunities

Focal therapy is an emerging treatment modality for localised prostate cancer that aims to reduce the morbidity seen with radical therapy, while maintaining cancer control. Focal therapy treatment strategies minimise damage to non-cancerous tissue, with priority given to the sparing of key structures such as the neurovascular bundles, external sphincter, bladder neck and rectum. There are a number of ablative technologies that can deliver energy to destroy cancer cells as part of a focal therapy strategy. The most widely investigated are cryotherapy and high-intensity focussed ultrasound. Existing radical therapies, such as brachytherapy and external beam radiotherapy, also have the potential to be applied in a focal manner. The functional outcomes of focal therapy from several phase I and II trials have been encouraging, with low rates of urinary incontinence and erectile dysfunction. Robust medium- and long-term cancer control outcomes are currently lacking. Controversies in focal therapy remain, notably treatment paradigms based on the index lesion hypothesis, appropriate patient selection for focal therapy and how the efficacy of focal therapy should be assessed. This review articles discusses the current status of focal therapy, highlighting controversies and emerging strategies that can influence treatment outcomes for the future.

Image visibility of cancer to enhance targeting precision and spatial mapping biopsy for focal therapy of prostate cancer

To assess the advantages of cancer image visibility when using multiparametric transrectal ultrasonography (TRUS) in potential candidates for focal therapy for prostate cancer. A total of 93 potential candidates for focal cryotherapy underwent grey-scale and Doppler TRUS-guided biopsy. All real-time TRUS images were recorded, allowing subsequent reviewing for the planning of targeted focal cryotherapy, and/or follow-up targeted biopsy. The spatial mapping of TRUS-visible lesions and targeted sampling areas were individually documented in schematic anatomic drawings of the prostate. Data from the baseline imaging-targeted biopsies were compared with systematic (non-targeted) biopsies. Of the 93 patients, 73 patients with low- to intermediate-risk disease were eventually considered to be candidates for hemi-ablative focal cryosurgery, i.e. cryoablation of one lobe. Among the 93 patients, a total of 681 biopsy cores were available for analysis, including imaging-targeted (n = 256, 37.5%) and systematic (n = 425, 62.5%) cores. Of the 256 targeted biopsy cores, 65% (n = 167) were positive for cancer, compared with 6.2% (26/425) in systematic (non-targeted) cores (P < 0.001). A total of 88% (82/93) of the biopsy-proven cancer index lesions were TRUS-visible. When comparing TRUS-visible with image-invisible index lesions, the cancer-involved core length was 6.1 vs 1.5 mm (P < 0.001), respectively. Furthermore, the percent of core with involved cancer was 48 vs 16% (P < 0.001), and the mean Gleason score was 7.0 vs 6.2 (P < 0.001). With increasing TRUS-visible lesion size (<10, 11-15, 16-20, >20 mm), cancer-involved core length and percent of core with cancer also significantly increased (P = 0.009 and P = 0.008, respectively). TRUS-guided targeted biopsies significantly improved the detection and staging of higher grade and larger volume cancer, compared with image-blind (non-targeted systematic) biopsies. Image visibility enhanced the precise targeting and accurate spatial mapping of cancer to help identify more appropriate candidates for focal therapy.

Endoscopic Vascular Targeted Photodynamic Therapy with the Photosensitizer WST11 for Benign Prostatic Hyperplasia in the Preclinical Dog Model

Vascular targeted photodynamic therapy with WST11 (TOOKAD® Soluble) is in phase III clinical trials of an interstitial transperineal approach for focal therapy of prostate cancer. We investigated the safety and efficacy of the endourethral route in the context of benign prostatic hyperplasia in the dog model. An optical laser fiber was positioned in the prostatic urethra of 34 dogs, including 4 controls. It was connected to a 753 nm diode laser at 200 mW/cm fluence, delivering 200 to 300 J. WST11 (5 to 15 mg/kg) was infused intravenously in 2 modes, including continuous, starting 5 to 15 minutes before and during illumination, or a bolus 5 to 10 minutes before illumination. Prostate ultrasound, cystourethrogram, urodynamics and histopathology were performed. Followup was 1 week to 1 year. Endourethral WST11 vascular targeted photodynamic therapy was uneventful in all except 1 dog, which experienced urinary retention but reached the 1-week end point. All prostates except those in controls showed hemorrhagic lesions. They consisted of 2 levels of concentric alterations, including periurethral necrosis with endothelial layer destruction and adjacent inflammation/atrophy with normal blood vessels. Prostatic urethral width increased as early as 6 weeks after treatment, while prostatic volume decreased, reaching 25% by 18 to 26 weeks. A parallel decrease in urethral pressure at 6 weeks lasted up to 1 year. We confirmed the vascular effect of endourethral WST11 vascular targeted photodynamic therapy. To our knowledge we report for the first time that the resulting periurethral necrosis led to significant, sustained widening of the prostatic urethra, accompanied by long-term improvement in urodynamic parameters. These findings support future clinical applications of this minimally invasive approach to benign prostatic hyperplasia.

There is no role for focal therapy in prostate cancer

There is no role for focal therapy in prostate cancer

Contrast-enhanced ultrasonography for real-time monitoring of interstitial laser thermal therapy in the focal treatment of prostate cancer

We report a case study of the application of contrast-enhanced ultrasonography (CEUS) for intraoperative monitoring of thermal ablation of a single focus of prostate cancer. A patient presented with biopsy-proven, solitary-focus, low-risk prostate cancer and was recruited into a clinical trial of interstitial laser thermal focal therapy. Multiparametric magnetic resonance imaging (MRI) was used to locate the single dominant focus, and photothermal ablation was performed at the tumour site under the guidance of transrectal ultrasonography. Transrectal CEUS using systemic bolus injections of the intravascular contrast agent Definity was performed immediately before, several times during and on completion of therapy. Lesions observed on CEUS were compared with treatment effect as measured by tissue devascularization on 1-week gadolinium (Gd)-enhanced MRI. Baseline images showed CEUS contrast-agent signal throughout the prostate. During and after treatment, large hypocontrast regions were observed surrounding the treatment fibres, indicating the presence of an avascular lesion resulting from photothermal therapy. Lesion size was found to increase during the delivery of thermal energy. Lesion size measured using CEUS (16 x 11 mm) was similar to the 7-day lesion measured using Gd-enhanced T(1)-weighted MRI. Focal therapy for prostate cancer requires both complete treatment of the dominant tumour focus and minimal morbidity. The application of CEUS during therapy appears to provide an excellent measure of the actual treatment effect. Hence, it can be used to ensure that the therapy encompasses the whole target but does not extend to surrounding critical structures. Future clinical studies are planned with comparisons of intraoperative CEUS to Gd-enhanced MRI at 7 days and whole-mount pathology samples.

The inhibition of ferrochelatase enhances 5-aminolevulinic acid-based photodynamic action for prostate cancer

The aim of this study was to clarify the mechanism of accumulation of 5-aminolevulinic acid (ALA)-dependent protoporphyrin IX (PpIX), ALA-photodynamic therapy (PDT)-induced cell death and enhanced efficiency by a ferrochelatase inhibitor in prostate cancer PC-3 cells. The accumulation of ALA-induced PpIX in PC-3 cells was observed by fluorescence microscopy and measured by flow cytometry analysis. The efficiency of ALA-PDT was analyzed by flow cytometry and assessed by cell death, caspase-3 activity and mitochondrial membrane potential. The ALA-PDT-promoting effects of ferrochelatase inhibitors, such as deferoxamine and NOC-18, were also analyzed. We confirmed the results obtained in vivo with an animal model using nude mice. ALA-induced PpIX accumulation increased in time- and ALA concentration-dependent manners. ALA-PDT decreased the levels of mitochondrial membrane potential, and induced cell death occurred by both apoptosis and necrosis. Inhibition of ferrochelatase by deferoxamine and NOC-18 led to increase of PpIX accumulation and enhanced effect of ALA-PDT in PC-3 cells. In vivo, the degeneration of tumor tissue by ALA-PDT was observed within a broader range and led to apoptosis and necrosis. This study demonstrated ALA-PDT induced PC-3 cell death by the mechanisms of both necrosis and apoptosis through a caspase-independent mitochondrial pathway. Inhibition of ferrochelatase enhanced these effects, suggesting that ferrochelatase played an important role in ALA-PDT. ALA-PDT could be a new modality for focal therapy of prostate cancer.