european urology 55 (2009) 1289–1292
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Platinum Priority – Editorial and Reply from Authors Referring to the article on pp. 1281–1288 of this issue
Nondestructive Testing in Urologic Oncology Shin Egawa * Department of Urology, Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan
The search for less invasive methods has been a major feature of modern, industrialized human society. Nondestructive testing (NDT) is the term used in industry for techniques used to evaluate the internal and/or external conditions of materials, components, and structures without damaging them or interfering with their continued usefulness. NDT is especially important for in-service inspection of high-cost and critical load-bearing structures such as bridges, tunnels, atomic power plants, the failure of which could have significant consequences. Among the wide variety of NDT technologies are mechanical and optical techniques, penetrating radiation, electromagnetic and electronic signatures, sonic and ultrasonic probes, smallarea chemical analysis, signal–image analysis, and techniques based on thermal detection or imaging. Medicine in the 21st century has benefited from similar advances. As innovative techniques are refined, less invasive procedures have now become the mainstay in the field of oncology. This merging of interest and laboratory technologies will provide further motivation and will facilitate development of less morbid, minimally invasive therapies. Radical prostatectomy (RP) is surgical treatment for prostate cancer (PCa) that removes the entire prostate gland as well as some of the tissue around it. The ultimate goal of any cancer surgery is complete extirpation of the tumor; however, positive surgical margins (PSM) in specimens from RP have been reported with disturbing frequency and may portend increased risk of eventual treatment failure [1–3]. Differences in the risk of recurrence
between focal (solitary) and extensive (multifocal) margins have been highlighted by some and disputed by others [1–3]. These differences in risk may be associated with extraprostatic extension of biologically aggressive tumors. Another possible cause may be inadvertent capsular incision at the tumor site during nerve-sparing procedures, which would thus be iatrogenic in origin. The surgeon’s ability to achieve complete resection and negative margin status may also be affected by the surgical technique used to achieve a function-preserving outcome. The reported PSM rates in localized PCa at a single, high-volume center are comparable for laparoscopic radical prostatectomy (LRP) and retropubic radical prostatectomy (RRP): 11.3% versus 11%, respectively . It thus appears that a magnified view with white light illumination provided by modern video technology in laparoscopic surgery may not contribute significantly to a reduction in PSM rates. This outcome may reflect both the maturity and the limitations of contemporary surgical techniques. Adam et al reported a multicenter, prospective, phase 2 trial of photodynamic diagnosis (PDD) for the detection of PSM during LRP or RRP . The PDD technique employed used 5-aminolevulinic acid (5ALA), a natural biochemical precursor of fluorescent porphyrins in various epithelia and cancerous tissues, to induce production of fluorescent protoporphyrin IX (PpIX) in cancer-positive areas of the specimen. The goal was to reduce PSM and, thus, to enhance complete resection rates. Nine of the 13 PSMs were recognized by PDD at the correct sites,
DOI of original article: 10.1016/j.eururo.2009.02.027 * Tel. +81 3 3433 1111; Fax: +81 3 3436 3787. E-mail address: [email protected]
0302-2838/$ – see back matter # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.
european urology 55 (2009) 1289–1292
which included 6 at the apex and 3 at the bladder neck. There were two false-positive and seven falsenegative sites. The overall sensitivity and specificity were 56.3% and 91.6%, respectively. This group is to be congratulated on their persistent, strenuous effort to explore the interesting avenue of PDD in urologic oncology. Additional questions, however, including the following specific issues, need to be addressed before introducing this procedure into routine practice. The mean preoperative prostate-specific antigen (PSA) level for those with PSMs in their study was about 30 ng/ml, possibly reflecting large tumors and advanced tumor status. All but one positive patient had pT3 disease. Most PSMs were probably extensive and may well have been easily detectable by conventional methods. Focal margins account for approximately one-third of all PSMs in our own institutional experience. Although the clinical significance of focal PSM is controversial, whether the PDD technique is sufficiently sensitive to detect minute PSMs without increasing the false-positive rate remains to be determined in future studies. This group’s previous study, which included 18 patients, indicates that PpIX fluorescence is predominantly located in cancerous tissue, independent of tumor grade . Heterogeneity in PpIX fluorescence intensity within the tumor is seen in glioblastoma, thus representing a potential cause of false negatives . This point must be more thoroughly investigated. The effects of other conditions such as chronic inflammation and the influence of beam angle on fluorescence excitation should also be examined. Ways to overcome observer dependency and to obtain objective assessment must also be investigated. With improved understanding of periprostatic anatomy, modified techniques for preservation of NVBs are now available. Intrafascial dissection can theoretically preserve up to 100% of NVBs, while the extrafascial approach invariably sacrifices NVBs (preservation close to 0%). Although interfascial dissection is often difficult because the absence of a cleavage plane means the fascia must eventually be torn, at least part of the NVB can be preserved. With the aid of state-of-the-art diagnostic technology and more advanced techniques, it will in time become possible to determine the optimal proportion of nerves to be preserved and to modify this decision intraoperatively according to the size, location, grade, and invasiveness of the tumor. Fluorescence-guided surgery may then have added practical impact. Real-time in vivo identification of tumor remnants in surrounding tissues during or immediately after dissection may allow the surgeon
to consider additional, wider resection to ensure complete tumor removal. Examination of frozen sections from resected tissue is time consuming and costly and may even be invasive at times and yet may not be sufficiently sensitive. This is especially true for apical tumors, where preservation of the longest possible urethral stump is desired to facilitate early recovery of continence. Such advances in diagnostic technology may also allow earlier decisions about adjuvant therapy in some cases; however, light absorption by heme present on surrounding tissues may hamper effective performance of PDD. Laparoscopic approaches with reduced pneumoperitoneum and, hence, less blood in the operative field may be advantageous in this regard. Although application of this method to focal surgery may be impracticable at present (intraparenchymal tumor location precludes fluorescent photodetection), this possibility should be explored in future studies. Ultimately, the efficacy of PDD after administration of 5-ALA in PCa surgery must be verified by randomized prospective trials that assess progression-free, cancer-specific, and overall survival. A method that would allow real-time differentiation of benign and malignant tissue in situ would clearly be of great clinical value. Although visual methods will continue to play a fundamental role in oncology, future technology will make it possible to intraoperatively identify tumors through an innovative microprobe attached to one of the arms of a surgical robot. The potential of a combination of laser-induced autofluorescence, white-light remission, and high-frequency impedance spectroscopy—all performed with a single probe—to identify benign and malignant prostate tissue ex vivo has recently been reported . Nanobioscience, coupled with microelectric–mechanical systems with nanopositioning capabilities, may facilitate further development. Strategic collaboration of the various NDT research communities, however, is essential to accomplishing this goal A multidisciplinary approach and joint efforts devoted to NDT will create immense value for future society. Our endeavor in this field of urologic oncology must, and will, continue. Conflicts of interest: The author has nothing to disclose.
References  Blute ML, Bostwick DG, Bergstralh EJ, et al. Anatomic site-specific positive margins in organ-confined prostate cancer and its impact on outcome after radical prostatectomy. Urology 1997;50:733–9.
european urology 55 (2009) 1289–1292
 Epstein JI, Pizov G, Walsh PC. Correlation of pathologic findings with progression after radical retropubic prostatectomy. Cancer 1993;71:3582–93.  Vis AN, Schro¨der FH, van der Kwast TH. The actual value of the surgical margin status as a predictor of disease progression in men with early prostate cancer. Eur Urol 2006;50:258–65.  Touijer K, Kuroiwa K, Eastham JA, et al. Risk-adjusted analysis of positive surgical margins following laparoscopic and retropubic radical prostatectomy. Eur Urol 2007;52:1090–6.  Adam C, Salomon G, Walther S, et al. Photodynamic diagnosis using 5-aminolevulinic acid for the detection of positive surgical margins during radical prostatectomy
in patients with carcinoma of the prostate: a multicentre, prospective, phase 2 trial of a diagnostic procedure. Eur Urol 2009;55:1281–8.  Zaak D, Sroka R, Khoder W, et al. Photodynamic diagnosis of prostate cancer using 5-aminolevulinic acid—first clinical experiences. Urology 2008;72:345–8.  Hefti M, von Campe G, Moschopulos M, Siegner A, Looser H, Landolt H. 5-aminolaevulinic acid-induced protoporphyrin IX fluorescence in high-grade glioma surgery. Swiss Med Wkly 2008;138:180–5.  Salomon G, Hess T, Erbersdobler A, et al. The feasibility of prostate cancer detection by triple spectroscopy. Eur Urol 2009;55:376–84. doi:10.1016/j.eururo.2009.03.059
Platinum Priority Reply from Authors re: Shin Egawa. Nondestructive Testing in Urologic Oncology. Eur Urol 2009; 55:1289–91 Georg Salomon a,*, Christoph Adam b a
University of Hamburg, Department of Urology, Hamburg, Germany b Belegabteilung, Urologie Klinikum Traunstein, Traunstein, Germany
Nondestructive testing (NDT) in medicine is a fascinating matter. The use of 5-aminolevulinic acid (5-ALA) for intraoperatively detection of residual cancerous tissue is described as a feasibility study  specificities up to 92% are encouraging to further investigate a photodynamic diagnostic (PDD) approach. Egawa states, that for those patients with a positive surgical margin (PSM), the mean preoperative PSA was 30 ng/ml in our study which would reflect large tumors . The aim of this study was to have at least an impression if PDD would detect tumor in an intraoperative setting. Therefore, patients who had at least an intermediate risk (PSA > 10 ng/ml and/or Gleason > 6) were enrolled in the study since the number of patients was limited to 40. Leaving out center 4, 6 PSMs (mean PSA: 51 ng/ ml) occurred which means that the other 3 centers had a mean PSA of 9 ng/ml for their 7 PSM cases. 6 out of 7 PSMs have been detected in centers 1–3 which indicates a detection rate of 86%. Therefore, DOIs of original articles: 10.1016/j.eururo.2009.02.027, 10.1016/ j.eururo.2009.03.059 * Corresponding author. University of Hamburg, Department of Urology, Martinistrasse 52, 20246 Hamburg, Germany. E-mail address: [email protected]
PDD might be suitable for patients for which a radical prostatectomy is performed in the majority of cases. On the other hand, in center 3, the majority of PSMs, which were at the NVB, were not detected by PDD but by frozen sections. This might be due to the fact that in intermediate risk patients for whom a nerve sparing procedure might be performed, the tumor foci at the margin are microscopic and would not be visible using PDD with low magnification. Without doubt, minimal tumor foci size visibility using PDD has to be clarified in sub-investigations for an open or laparoscopic RP. Additionally, sub-investigations are underway to determine the ‘‘real’’ sensitivity and specificity of PDD in this cohort of patients. Resected prostates have been cut into slices according to the Stanford protocol, macrophotos have been made under PDD and margin rates as well as intraprostatic findings of tumor lesions have to be matched with histopathological results for all foci. This study might elucidate if, for example, chronic inflammation might be PDD positive and would misguide the surgeon to resect functional tissue which should remain in situ. Hypothetically, the combination of laser induced autofluorescence in combination with electrical impedance measurement and 5-ALA might alter the discrimination of malignant and benign tissue in situ . This is still hypothetical and should also be investigated. If cancer specific mortality can be lowered or more functional tissue might be preserved due to PDD is unclear. In addition, not to disregard the power of photodynamic therapy (PDT), usage of 5-ALA might also eradicate residual cancerous tissue by phototoxicity induced by illumating the operative situs. Zaak et al. described the possibility