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3rd Meeting of the European Society of Oncological Urology (ESOU) OUTLINE LECTURES CONSERVATIVE VS RADICAL SURGERY FOR RENAL CELL CARCINOMA H. Van Poppel Leuven, Belgium Introduction RCC accounts for ",3% of all adult malignancies; with the increasing number of incidentally detected kidney tumours there has been a migration to smaller, lower-stage tumours. The TNM classification has recently been adapted [1] to differentiate between tumours measuring;4 cm (Tl a) and 4-7 cm (Tl b). In the management of these small tumours there has been a definite trend away from open radical nephrectomy (ORN) toward nephron-sparing surgery (NSS) and minimally invasive approaches. Radical Nephrectomy Surgical resection remains the cornerstone of treatment for RCe. ORN was the 'gold standard' of care for localized RCC against which all other forms of surgery for RCC were measured. This standard has been more than challenged by the introduction of elective NSS for small renal tumours and laparoscopie radical nephrectomy (LRN) for lesions not amenable to NSS. Radical nephrectomy consists of the early ligation of the renal artery and vein, removing the kidney outside Gerota's fascia, and removing the ipsilateral adrenal gland and the regionallymph nodes. Years ago it was suggested and more recently argued again that removing the ipsilateral adrenal gland is not always necessary, in the absence of radiographic adrenal enlargement, unless the malignancy either extensively involves the kidney or is in the upper portion of the kidney [2]. However, adrenalectomy should remain part of radical nephrectomy for RCC of >5 cm, as the risk of unexpected microscopie invasion of the adrenal has been shown to be as high as 7.5% [3.4J. Regional lymph node extension is associated with poor survival. Lymphadenectomy allows for more accurate pathological staging but its therapeutic value remains controversial [sj. Nevertheless, there may be a subset of patients with micrometastatic Iymph node involvement who might benefit from prophylactic Iymphadenectomy [6,7J. When the Iymph nodes are enlarged on imaging, a lymphadenectomy can be useful as up to 30% of patients might have inflammatory nodal enlargement only [8]. The European Organization of Research and Treatment of Cancer (EORTC) trial 30881, comparing the results of radical nephrectomy with or without lymphadenectomy, will be analysed soon and should solve the controversy about the benefit of a 'preventive' lymph node dissection [9J The surgical approach for radical nephrectomy is determined by the size and location of the tumour, and by patient-related factors. The open procedure is usually done through a transperitoneal (midline or chevron) incision to allow early access to the vessels. Some still prefer an extended subcostal extraperitoneal or transperitoneal incision [10]. Disadvantages of a transperitoneal approach are the long er postoperative ileus and the possible late intra-abdominal adhesions. A thoracoabdominal approach is seldom required but can be used in patients with large upper pole tumours. LRN (transperitonealor retroperitoneal) has developed tremendously over the past decade to become a feasible and the best tolerated approach for localized T1-T2 renal tumours that are not amenable to NSS. In these patients LRN is becoming the standard [11J. The benefits of decreased postoperative pain, shortened hospital stay, quicker convalescence and improved cosmesis are clear, and long-term oncological results are equivalent to those of ORN [12]. 13 -15 January 2006, Brussels, Belgium 1 3rd Meeting of the European Society of Oncological Urology (ESOU) A follow-up after radical nephrectomy is recommended to detect local recurrence and distant metastases, to permit additional treatment when indicated and if possible. There is no consensus on an optimum follow-up regimen. The risk of postoperative recurrent malignancy is stage-dependent and follow-up should therefore be tailored to the pathological risk factors for recurrence, e.g. stage, size, grade, histological subtype, nodal status and vascular invasion [13,14]. NSS NSS was initiated and elaborated in Europe; the enthusiasm for its use has been stimulated by advances in renal imaging, improved surgical techniques and methods to prevent ischaemie renal injury, better postoperative management and excellent longterm cancer-free survival data. NSS is now being considered to enable the preservation of renal function with exceptional local recurrences, and high patient satisfaction [15]. The indications for NSS can be categorized as absolute (or imperative), relative or elective. The absolute indications are those where radical nephrectomy would render the patient anephric (either anatomically or functionally) with a subsequent need for dialysis, i.e. bilateral tumours, tumours in a solitary kidney, or significant renal failure. Relative indications are those in which the contralateral kidney has pre-existing renal disease or is at substantial risk of future compromise, e.g. renal artery stenosis, reflux, stones, diabetes or hypertension. Currently, smaller tumours, amenable to so-called 'elective' partial nephrectomy, are detected frequently in the presence of a normal contralateral kidney. These indications are still controversial. Although many renal lesions can technically be resected by tumorectomy, such surgery should remain restricted to patients who have easily resectable lesions. These indications become increasingly accepted, although the oncological equivalence of partial and radical nephrectomy has not vet been shown in a controlled randomized trial (Van Poppel H: Prospective randomized Phase 111 study comparing radical surgery to elective kidney sparing surgery for low stage renal cell carcinoma. EORTC Trial 30904). For tumorectomy a simple enucleation, an excavation or enucleo-resection with a rim of healthy parenchyma, apolar nephrectomy or a heminephrectomy can be used [16]. The renal vessels are identified and controlled, and the kidney fully exposed. When a complicated or time-consuming resection is anticipated, temporary clamping of the hilus and cooling can be applied. The renal capsule is incised and blunt/sharp dissection used to remove the tumour, along with a margin of normal parenchyma. Just a few millimetres of normal parenchyma were shown to be enough to guarantee safe resection margins [17]. Arterial or venous bleeding is controlled with suture ligatures, and openings of the pelvi-calyceal system are meticulously closed. When the parenchymal defect cannot be closed, haemostatic agents can be used to fill the defect, to provide additional haemostasis. Intraoperative ultrasonography to either delineate the intraparenchymal extent of the tumour, or to detect secondary tumours, and intraoperative frozen-section analysis for the surgical margins [18]. have been proposed but are not routinely applied. The most important complications of partial nephrectomy are haemorrhage, urinary fistula and renal insufficiency. Complications are obviously more frequent in imperative resections. Bleeding can occur in the perirenal space and is recognized by an adequately placed suction drain.lntrarenal haemorrhage, and severe haematuria, result from arteriocalyceal or arteriovenous fistula, or pseudo-aneurysm formation. Both types 13 -15 January 2006, Brussels, Belgium 2 3rd Meeting of the European Society of Oncological Urology (ESOU) of postoperative bleeding can be efficiently treated by super selective embolization. When urinary leakage is excessive the most important factor in solving the problem is adequate suction drainage to avoid urinoma formation. Placing a JJ ureteric stent or a nephrostomy can be helpful. Prolonged clamping of the hilus with no cooling can result in tubular necrosis, necessitating temporary haemodialysis. Damage to the intima of the renal artery by an inappropriate clamp in an atherosclerotic patient can also be responsible for infarction of the renal remnant, with definitive renal insufficiency [19]. The technical success rate with NSS is excellent, and long-term patient survival rates are comparable to those obtained after radical nephrectomy, particularly for low-stage RCC. The major disadvantage of NSS is the risk of postoperative local tumour recurrence in the remnant kidney, which has occurred in up to 10% of patients. This can be a result of incomplete resection (Iocal recurrence) after simple enucleation, or when the surgical margin was not clear of tumour, or to multifocality (kidney recurrence). In both situations a second operation, mostly radical nephrectomy, can still offer cure. NSS provides effective long-term treatment for patients with localized RCC when preserving renal function is clinically important. It is becoming an increasingly accepted approach in patients who have a single, small («4 cm) and easily resectable RCC and a normal contralateral kidney [20]. Whether elective NSS should be proposed in larger and more centrally located tumours remains highly questionable, and the feasibility of difficult NSS reported by some expert centres cannot be an argument to advocate this approach in current urological practice. After partial nephrectomy the follow-up should mainly be focused on the remnant kidney, to detect any local or kidney recurrence in the early stages. Local recurrence should be sought after pure enucleation (a5 in imperative cases) and kidney recurrence after resection of a clear cell RCC in genetic syndromeslike Von Hippel Lindau, or of a papillary RCC, both being more often multifocal or bilateral. Patients who develop a recurrence with no signs of metastases will be considered for salvage surgical treatment. Surveillance for recurrence must be tailored according to the initial pathological tumour type and stage, and to the surgical technique applied, with ultrasonography and abdominal CT. A5 long as NSS is not the unequivocal 'standard' treatment for RCC, a regular follow-up remains warranted [19]. Minimally Invasive NSS Open partial nephrectomy, with its excellent 5 and 10 year oncological follow-up results, is the reference standard against which all other NSS alternatives must be compared. The new minimally invasive nephron-sparing alternatives can essentially be divided into three categories: excision (laparoscopic partial nephrectomy, LPN), probe ablation (e.g. cryotherapy and radiofrequency ablation, RFA), and noninvasive ablation (highintensity focused ultrasound, HIFU). The technique of LPN for treating RCC is still under development. Although both intraand retroperitoneal LPN have been successful it has been difficult to reproduce the essential elements of open partial nephrectomy using contemporary laparoscopic instrumentation. Despite advanced techniques, including the use of a harmonic scalpel and biological tissue adhesives such as fibrin glue, LPN has resulted in longer operations and higher complication rates than open partial nephrectomy. The initial experience suggests that LPN can be used for small exophytic renal tumours, with adherence to established principles and techniques of the open surgical approach. Although both the instrumentation and technique are being refined, it is too early to 13 -15 January 2006, Brussels, Belgium 3 3rd Meeting of the European Society of Oncological Urology (ESOU) consider LPN a reproducible operation for cancer that is appropriate outside a specialized centre [21]. Laparoscopic cryoablation could represent a reasonable alternative as the kidney is an anatomically favoured site for cryoablative therapy, because it can readily be dissected from adjacent organs and usually gives rise to a unifocal malignancy. During cryoablation the tumour is supercooled to a core temperature of <-40°C using a liquid nitrogen-based cryoprobe. Normal and neoplastic renal tissues are ablated and rendered necrotic at -20°C. To ensure complete tumour destruction the advancing ice-ball is monitored laparoscopically and ultrasonographically [22]. A major criticism of the technique is that histological documentation of complete tumour destruction is not currently available. Longterm clinical and radiographic follow-up of these patients is ultimately needed to validate the efficacy of this minimally invasive approach for treating renal malignancy; 5year follow-up data should be available in the near future. Newer energy sources for tumour ablation include HIFU, interstitial RFA. and laser and microwave coagulators. These methods may eventually permit tumour destruction by minimally invasive techniques and completely extracorporeal methods. Theoretical and experimental evidence indicate that the primary mechanism of tissue destruction by both RFA and HIFU is thermonecrosis. These methods induce cavitary defects in animal and human renal tissues, safely and reproducibly, while limiting collateral injury to the unaffected parenchyma [22]. To gain a place among the options of nephron-sparing approaches, HIFU and RFA must give clinical and pathological success rates approaching that of open partial nephrectomy. Although renal RFA has the potential to further minimize morbidity, serious concerns remain about the completeness of cancer cell death and the reliability of intraoperative monitoring. Noninvasive technological advances like HIFU could have considerable potential for the future [23]. REFERENCES 1.Sobin LH, Wittekind C-H. TNM CIassification of Ma/ignant Tumors. Chichester: WileyLiss, 2002: 193-5 2. Tsui KH, Shvarts 0, Barbaric Z, Figlin R, deKernion JB, Belldegrun A. Is adrenalectomya necessary component of radical nephrectomy? UCLA experience with 511 radical nephrectomies. J Uro/ 2000; 163: 437-41 3. Li GR, Soulie M, Escourrou G, Plante p, Pontonnier F. Micrometastatic adrenal invasion by renal carcinoma in patients undergoing nephrectomy. Br J Uro/1996; 78:8268 4. Von Knobloch R, Seseke F, Riedmiller H, Gröne HJ, Walthers EM, Kälble T. Radical nephrectomy for renal cell carcinoma: Is adrenalectomy necessary? Eur Uro/1999; 36: 303-8 5. Schafhauser W, Ebert A, Brod J, Petsch 5, Schrott KM. Lymph node involvement in renal cell carcinoma and survival chance by systematic Iymphadenectomy. Anticancer Res 1999; 19: 1573-8 6. Herrlinger A, Schrott KM, Schott G, Sigel A. What are the benefits of extended dissection of the regional renal Iymph nodes in the therapy of renal cell carcinoma? J Uro/1991; 146: 1224-7 7. Giuliani L, Gilberti C, Martorana G, Rovida S. Radical extensive surgery for renal cell carcinoma. J Uro/1990; 143: 468-74 8. Studer UE, Scherz 5, Scheidegger J eta/. Enlargement of Iymph nodes in renal cell carcinoma is often not due to metastases. J Uro/1990; 144: 243-5 13 -15 January 2006, Brussels, Belgium 4 3rd Meeting of the European Society of Oncological Urology (ESOU) 9. Blom JHM, Van Poppel H, Maréchal JM et a/. Members of the EORTC Genitourinary group. Radical nephrectomy with and without Iymph node dissection: preliminary results of the EORTC randomized Phase 111 protocol 30881. EurUro/1999; 36: 570-5 10. Kirkali Z, Van Poppel H, Tuzel E eta/. A prospective survey of surgical approaches in clinically localized renal cell carcinoma. Uro/ Onco/ 2002; 2: 169-74 11. Abbou CC, Cicco A, Gasman D. Retroperitoneallaparoscopic vs open radical nephrectomy. J Uro/1999; 161: 1776-80 12. Dunn MD, Portis AJ, Shalhav AL. Laparoscopie versus open radical nephrectomy: a 9-year experience. J Uro/ 2000; 164: 1153-9 13. Levy DA,Slaton JW, Swanson DA, Dinney CP. Stage specific guidelines for surveillance after radical nephrectomy for local renal carcinoma. J Uro/1998; 159: 1163-7 14. Van Poppel H, Vandendriessche H, Boel K. Microscopie vascular invasion is the most relevant prognostica tor after radical nephrectomy for clinically nonmetastatic renal cell carcinoma. J Uro/1997; 158: 45-9 15. Van Poppel H. Nephron-sparing surgery in renal cell carcinoma. Braz J Uro/2000; 26: 342-53 16. Van Poppel H, Deroo F, Joniau S. Open surgical treatment of localised renal cell ca neer. EAU Update Series 2003; 1: 220-5 17. Piper NY, Bishoff JT, Magee C eta/. Is a 1 cm margin necessary during nephronspa ring surgery for renal cell carcinoma? Ur%gy 2001; 58: 849-52 18. Campbell SC, Fichtner J, Novick AC eta/. Intraoperative evaluation of renal cell carcinoma: a prospective study of the role of ultrasonography and histopathological frozen sections. J Uro/1996; 155: 1191-5 19. Van Poppel H, Bamelis B, Oven R, Baert L. Partial nephrectomy for renal cell carcinoma can achieve long-term tumor control. J Uro/1998; 160: 674-8 20. Gilbert SM, Russo p, Benson MC, Olsson CA, McKirnan JM. The evolving role of partial nephrectomy in the management of renal cell carcinoma. Current Onco/ Reports 2003; 5: 239-44 21. Gill IS, Matin SF, Desai MM. Comparative analysis of laparoscopie vs open partial nephrectomy for renal tumors in 200 patients. J Uro/2003; 170: 64-8 22. Gill IS, Novick AC, Soble JJ. Laparoscopie renal cryoablation: initial clinical series. Urology 1998; 52: 54351 23. Abreu SC, GiIiIS. Renal cell carcinoma: modern surgical approach. Current Opinion Uro/2003; 13: 439-44 Abbreviations: EORTC, European Organization of Research and Treatment of Cancer; HIFU, high-intensity focused ultrasound; NSS, nephron-sparing surgery; RFA, radiofrequency ablation; ORN, LRN, open, laparoscopie, radical nephrectomy; LPN, laparoscopie partial nephrectomy. 13 -15 January 2006, Brussels, Belgium 5 3rd Meeting of the European Society of Oncological Urology (ESOU) DEVELOPMENTS IN ORGAN PRESERVING TREATMENTS FOR RENAL CELL CANCER: OPEN SURGERY H. Van Poppel Leuven, Belgium Z. Kirkali Izmir, Turkey Recent trends in cancer surgery have shown that the same cure rates can be achieved with more organ and tissue sparing techniques and multimodal approaches. Developments in technology and better patient care now render most operations to be possible. In the past radical nephrectomy for renal cell carcinoma (RCC) used to save many lives because most of the patients were presenting at advanced stages. Thanks to modern imaging techniques and health awareness of the public, today, most of the patients are presenting with small incidentally detected renal masses. Apart from patients requiring organ preservation for absolute and relative indications, most patients today are enjoying the benefits of nephron sparing surgery (NSS) in an elective setting. The crucial step in NSS is to get control of the renal vessels first and to expo se the whole kidney to look for satellite cortical lesions. A safe rim of healthy tissue has to be removed together with the tumor. AH bleeders are sutured, and if the collecting system is entered, it should be repaired. The parenchyma is sutured for approximation with absorbable sutures. The long term results with NSS show acceptable oncological outcome. The rate of complications of NSS has dramatically decreased with better patient selection, improved techniques and better management. All patients should be informed of the complications, recurrence rates and follow-up conditions. The advances in laparoscopic techniques now render NSS possible in selected patients. However, this is an extremely challenging operation, and can only be performed in expert hands. New technology is also emerging utilizing new forms of energy for tumor destruction and ultimately for nephron sparing approaches in localized RCC. As we are detecting more small renal masses, some of which are benign, NSS will remain to be the treatment of choice for these patients. 13 -15 January 2006, Brussels, Belgium 6 3rd Meeting of the European Society of Oncological Urology (ESOU) THE OPTIMAL MARGINS IN NEPHRON-SPARING SURGERY H. Van Poppel Leuven, Belgium It was in 1950 that Vermooten [1] described how conservative surgery for certain renal tumors had to be performed. One of the important issues was that the tumor excision needed a margin of healthy parenchyma of 1 cm [1]. Meanwhile, nephron-sparing surgery has undergone an enormous shift from absolute, imperative indications to elective indications, i.e. in the presence of a normal contralateral kidney. In the latter category patients are selected with mostly low-stage, low-grade tumors that might not need a 1 cm margin to be cured. Moreover, such a margin requires the sacrifice of more healthy parenchyma than might be necessary to guarantee oncological cure. The results of partial nephrectomy for small renal cell carcinomas are excellent and local recurrences have been documented to occur in less than 1 % of cases [2]. In most series the authors have performed either a wedge resection in healthy parenchyma, an enucleoresection or excavation where the tumor is resected with a rim of just a few millimeters of normal tissue or finally a pure enucleation relying on the presence and intactness of a tumoral pseudocapsule. In reports from expert centers it is now advocated to intraoperatively verify the absence of malignancy in the remaining portion of the kidney by frozen-section examinations of biopsy specimens obtained at random from the renal margin of excision [3]. Although this might indeed be helpful one should realize that false-positive and false-negative results can be obtained. Potential pitfalls in the frozen section evaluation of parenchymal margins in nephron-sparing surgery have been described, emphasizing the difficulty of distinguishing crushed tubules and detached atypical cells from really malignant cells. Benign renal tubules can indeed be mistaken for neoplastic ones and damaged minifragments of renal parenchyma that on top have freeze artifacts can make interpretation by the pathologist impossible [4]. When the pathologist reports malignancy the is would indicate possibly unnecessary more-extensive resection or radical nephrectomy. On the other hand, the meaning of a negative frozen section is equally not unambiguous. Reports on partial nephrectomy cases where frozen sections of the margins were negative, while the definitive margin was positive, have been published. Only a minority of these patients ever developed an isolated local recurrence and therefore the importance of the assessment of the surgical margins remains unclear [5-7]. No higher recurrence rate was noticed in patients with positive margins on definitive pathology and salvage nephrectomy performed in some of these cases could not find residual tumor in the remnant kidney. While it is obvious that complete excision is mandatory, the size of the margin remains debated. A study on radical nephrectomy specimens showed that more than 30% of small renal tumors (~4 cm) did not have an intact pseudocapsule and in 20% there was obvious cancerous growth beyond the pseudocapsule reaching as far as 0-5 mm into the healthy parenchyma. Therefore these authors suggested that, although a 10-mm margin may be too large, a safe excision necessitates a margin of 5 mm [8]. This is actually not what is done in clinical practice. On the basis of retrospective analyses it appears that a norm al tissue margin of just 1 mm or more may be adequate to prevent local recurrences from renal cell carcinoma [6]. The margin status is therefore the most important issue and not the margin size [7]. No association was found between the width of the resection margin and disease progression even after an extensive follow-up of 8.5 years [9]. We continue to discourage pure enucleation and emphasize that a rim of normal renal tissue must surround the tumor in elective kidney-sparing surgery. The use of routine frozen section is not advocated and enucleoresection remains the first choice. 13 -15 January 2006, Brussels, Belgium 7 3rd Meeting of the European Society of Oncological Urology (ESOU) Partial nephrectomy is becoming standard for renal tumors less than 4 cm and further expansion of the indications of partial nephrectomy can be expected [10]. Careful patient selection and application of oncologically safe principles are most important to guarantee a successful nephron-sparing approach for renal cell carcinoma. References 1.Vermooten V. Indications for conservative surgery7in certain renal tumors: a study based on the growth pattern of the clear cell carcinoma. J Urol 1950; 64:200-202. 2.Van Poppel H, Bamelis B, Oyen R, Baert L. Partial nephrectomy for renal cell carcinoma can achieve long-term tumor contro!. J Uro11998; 160:674-678. 3.Novick AC. Nephron-sparing surgery lor renal cell carcinoma. Annu Rev Med 2002; 53:393-407. 4.MeHale T, Malkowiez SB, Tomaszewski JE, Genega EM. Potential pit/alls in the frozen section evaluation ol parenchymal margins in nephron-sparing surgery. Am J CHn Pathol 2002; 118:903-910. 5.Zigeuner R, Ouehenberger F, Pummer K, et al. Long-term results of nephronsparing surgery for renal cell carcinoma in 114 patients: risk factors for progressive disease. Br J Urol lnt 2003; 92:567-571. 6.Piper NY, Bishoff JT, Magee C, et al. Is a 1-em margin necessary during nephronsparing surgery for renal cell carcinoma? Urology 2001; 58:849852. 7.Sutherland SE, Resnick MI, Maclennan GT, Goldman HB. Does the size of the surgical margin in partial nephreetomy lor renal cell cancer really matter? J Urol 2002; 167:61-{)4. 8.Li OL, Guan HW, Zhang OP, et al. Optimal margin in nephron-sparing surgery lor renal cell carcinoma 4 cm or less. Eur Urol 2003; 44:448-451. 9.Castilla EA, Liou LS, Abrahams NA, et al. Prognostie importance of resection margin width after nephron-sparing surgery for renal cell carcinoma. Urology 2002; 60:993-997. 10.Patard JJ, Shvarts 0, Lam JS, et al. Salety and efficacy of partial nephrectomy lor all T1 tumors based on an international rnulticenter experience. J Urol 2004; 171:21812185. 13 -15 January 2006, Brussels, Belgium 8 3rd Meeting of the European Society of Oncological Urology (ESOU) CRYO-ABLATION AND THE TREATMENT OF SMALL TUMOURS P. Whelan, Leeds UK The routine use of ultrasonography in upper abdominal examination has, over the last decade or more yielded an increasingly high diagnosis of small renal lesions. Whilst initially these lesions (small taken as been less than 4cm in diameter in this context) were treated conventionally by radical nephrectomy. Up to 15% of small lesions, especially those less than 2cm in some series, were found to be entirely benign. This led to increasing utilisation of partial nephrectomy, not only to deal with small true tumours but also in dealing with benign lesions and thus preserving a significant part of renal function. A secondary consideration has been many of these lesions have been found in patients who are unfit for extirpative surgery be it a radical nephrectomy or partial nephrectomy. Therefore, other means of controlling, or destroying this lesion had been sought rather than the hitherto conventional method which had been observation alone. These two reasons have combined for further re-exploration of another of modalities which can lead to insitu ablation of small tumours whilst minimising the harmful effects to surrounding healthy renal tissue. One of these modalities is cryo- ablation. Cryo-probse can achieve tissue temperature as low as -190ºc by exploiting the JouleThompson. Typically compressed argon gas is allowed to expand to a small orifice producing temperatures well below those required to ablate normal renal tissue and cancer cells considered respectively to be – 19.4ºc and - 40ºc. Renal cyro-ablation can be delivered using either an open surgical technique with placement of the probe in the appropriate place, a laparoscopic approach, or via a percutaneous procedure. The first two procedures can be actively observed with ultrasonography whilst a percutaneous procedure may utilise ultrasonography or act axel MRI or CT scans. The ice-ball can be developed using a single larger or several smaller cry probes and both their size and the number may be dependent on the renal mass. Following the techniques used in the prostate a double free cycle is most commonly utilised. There are at present a combined total of 346 reported cases (Kyle J et al) with a mean follow up of 30.8 months. The tumour persistence or recurrent rate is just under 5% and the complication rate just over 10%. This technique shows early promise, the almost 11% morbidity rate shows that it is not without its complications especially in patients that may already have a significant burden of co-morbid disease. 13 -15 January 2006, Brussels, Belgium 9 3rd Meeting of the European Society of Oncological Urology (ESOU) EORTC LECTURE WHAT IS NEW IN METASTATIC RCC? Z. Kirkali, Izmir Turkey The outcome of patients with metastatic renal cell cancer (mRCC) is grim. Most patients do not show long term response to any treatment, and many die within a year. Recently, there have been many developments in this field and there appears to be some hope for the treatment of patients with mRCC. The EORTC GU Group has conducted a number of trials in patients with mRCC. The first one is the trial where nephrectomy was compared with nephrectomy + interferon alpha (IF α). This trial, a similar trial by SWOG and their combined analysis showed a survival benefit for nephrectomy in patients with good performance status. In another Phase II/III study of 320 patients, we have shown improved objective response rate (19% versus 6%) and improvement in overall survival from 13 to 17 months by the addition of 13-cis- retinoic acid to IFN- therapy. Another EORTC trail comparing IF α with the triple combination is still ongoing in the UK. Tumor hypoxia plays an important role in RCC. The VHL gene which is mutated in majority of patients with sporadic RCC does not produce the pVHL or produces a nonfunctioning pVHL. This in the end causes activation of some hypoxia inducible pathways and expression of VEGF and angiogenesis. Some new compounds specifically targeting certain steps of these pathways have shown to be effective in mRCC. Two of these compounds are PTK787/ZK222584 and BAY-43906 (Sorafenib). The EORTC GU Group is starting a Phase II trial with PTK787 which is a tyrosine kinase inhibitor and an antiangiogenic agent. The EORTC GU Group is also joining forces with the MRC of UK in a Phase III trail comparing Sorafenib with placebo in patients with resected primary RCC at high or intermediate risk of relapse. These new compounds are promising agents in the treatment of patients with mRCC. 13 -15 January 2006, Brussels, Belgium 10 3rd Meeting of the European Society of Oncological Urology (ESOU) CURRENT ROLE OF PSA KINETICS IN THE MANAGEMENT OF PATIENTS WITH PROSTATE CANCER L. Klotz Toronto, Canada S. Teahan Introduction Prostate-specific antigen (PSA) is the most widely used tumour marker in clinical practice. The value of PSA in identifying patients at increased risk of prostate cancer is controversial. PSA screening has resulted in a dramatic stage migration towards small volume cancer. Stamey and others have therefore questioned the utility of an isolated PSA reading in the context of prostate cancer diagnosis (1). The ongoing debate over PSA measurement has only recently begun to incorporate the additional value derived from using PSA kinetics for patient decision-making.. That is the focus of this review. Prostate specific antigen velocity Prostate specific antigen velocity (PSA-V) is the absolute rate of change in PSA over time. The original description, by Carter et al., differentiated between men subsequently diagnosed with prostate cancer who had a PSA-V of 0.75ng/ml per year or greater, and those who had BPH or no appreciable prostatic disease (PSAV < 0.75ng/ml/yr) (2). This cut-off of 0.75ng/ml/yr was 95% specific and 72% sensitive for a subsequent diagnosis of prostate cancer. These differences were demonstrable for up to 5 years before diagnosis. Data from the National Prostate Cancer Detection Project confirmed the specificity of a PSA velocity of 0.75 ng/ml/yr in detecting prostate cancer (96%), albeit with a somewhat reduced sensitivity of 55% (3). Subsequently this value became widely accepted as a trigger for biopsy in those men who had sufficient PSA data to assess PSA-V. A more recent analysis (AUA, 2005) of the Baltimore Longitudinal Studies of Aging cohort, reported that a PSA velocity of > 0.16 ng/ml/year identified men at considerably higher risk of prostate cancer death. In that series, 8% of men in this group went on to die of prostate cancer 15-20 years later, compared to 0-1% of men with a PSA velocity < 0.16ng/ml/yr. The difficulty with this approach is the confounding effect of the biologic variability of PSA. In the absence of disease, day to day variation in PSA has been estimated at 34%. Indeed an increase between 2 consecutive PSA levels that is less than 20-46% may be due to biological and analytical variation alone (4). Infection and prostatic manipulation can also affect PSA levels (5). It follows that variation is often substantially greater than 0.75 ng/ml/year, (much less 0.2 ng/ml/year) and may result in the identification of many patients as having ‘rapid rise’, when what is being observed is biological variation. In undiagnosed men, a minimum of 3 measurements acquired over a 1.5-2 year interval should be used to minimise the effects of “normal” variation and noncancer related causes (6). More recent data from the Polyp Prevention Trial reaffirm the importance of confirmation of an isolated elevation in PSA level before proceeding with further testing (7). Among those with an elevated age-specific PSA in that study, values returned to normal in 55% of men at one or more subsequent visits during 4 years of follow-up. In North America, the population characteristics of prostate cancer and PSA have changed drastically. Patients now have smaller volume cancers, lower PSAs, and lower stage disease. Therefore data based on populations studied prior to the mid-90s may not be generalizable. Nonetheless, the evidence consistently demonstrates that there is a significant difference in PSA kinetics between populations with and without prostate cancer. 13 -15 January 2006, Brussels, Belgium 11 3rd Meeting of the European Society of Oncological Urology (ESOU) PSA-V and screening Two studies address the utility of PSA velocity as a screening tool, in men with a PSA of 4ng/ml and less. Utilising a PSA velocity cut-off of 0.1ng/ml/yr, 81% and 85% of cancers were correctly identified in the Baltimore Longitudinal Study of Ageing (BLSA) and the European Research Study of Prostate Cancer (EPSPC). (8,9). However, using this value, specificity dropped to 50% and 18% respectively. The disparity in the specificity rates in these two studies likely reflects design differences. The BLSA was an observational study and the data presented in this paper refers to results obtained over two decades. Many of the cancers were detected in the pre-PSA era (hence more likely to be advanced). The European screening study analyses data collected over a four-year period only. It is possible that men currently thought to be cancer free in this cohort will develop prostate cancer with longer follow-up. When analysing PSA-V data three or more PSA values should preferably be used. However clinicians often encounter situations where a suboptimal number of measurements are available. Riffenberg et al have described “early PSA velocity” (EPSAV) (defined as the change from the first to second PSA reading standardised as PSA change per year) which can be used in such situations (10). In this large single-centre retrospective study, a highly significant difference in EPSAV between those patients whose PSA subsequently increased greater than 4ng/ml and who had a positive biopsy result and those who had neither an increase in PSA or positive biopsy was demonstrated. PSA V: A marker of disease biology? The role of pre-operative PSA-V in determining subsequent risk of death from prostate cancer has been analyzed in a key recent publication of 1095 men with clinically localized prostate cancer. D’Amico reported that a preoperative PSA-V of greater than 2ng/ml/year, calculated by linear regression, was associated with lymph-node metastases, an advanced pathological stage and high-grade disease (11). This threshold level in PSA-V was also associated with a significantly shorter time to recurrence, death from prostate cancer, and death from any cause. Strikingly, men with a PSA rise of > 2.0 ng/ml had prostate cancer specific mortality rates 9 times those with a PSA-V < 2ng/ml. Nonetheless, with a mean follow up of 5 years, less than 10% of patients with a rapid PSA velocity actually died of prostate cancer in this series. These findings are in stark contrast to those presented by Freedland, who found preoperative PSA velocity did not predict biochemical recurrence or adverse pathological features post radical prostatectomy (12). From a cohort of 331 patients who had undergone RRP, 86 patients were identified who had sufficient PSA data to allow estimation of pre-operative PSA-V. Pre-operative PSA-V was not predictive of margin positivity, seminal vesicle involvement or capsular penetration (p=0.30). Neither was there an association between pre-op PSA velocity and surgical Gleason score (p>0.36). This later study was lacking in power, and direct comparisons between these studies are problematic. The D’Amico data, if confirmed, should change practice. Of men with high-grade disease and a PSA-V of greater than 2ng/ml, 28% died of their disease within 7 years of surgery. This means that a) these patients are candidates for aggressive therapy, even if they have “unfavourable” clinical parameters or significant co-morbidity, and b) as surgery alone is insufficient for a considerable proportion; adjuvant therapies need to be considered in this group. PSA doubling time PSA doubling time (PSA-DT) is the time required for the PSA to double in value. Pearson and Carter observed that, in patients with prostate cancer, PSA increases initially in a 13 -15 January 2006, Brussels, Belgium 12 3rd Meeting of the European Society of Oncological Urology (ESOU) linear manner followed by an exponential phase (13). If it is assumed that PSA is increasing exponentially at the time of diagnosis then doubling time can be expressed as PSA-DT = natural log 2 (0.693) / where is the slope of log PSA vs. time (14). This method uses all PSA values available to determine doubling time. A short doubling time is a surrogate for rapid tumour growth and a longer doubling time implies a more indolent tumour. DeKernion was the first to correlate doubling time with clinical behaviour in patients with biochemical failure post RRP, in whom he found that doubling times of 4.3 and 11.7 months were associated with metastatic and locally recurrent disease respectively (15,16). In a similar setting Pound demonstrated that a PSA-DT of less than or equal to 10 months was predictive of the probability and time to the development of metastatic disease (14). Similar data have also been demonstrated following definitive radiotherapy (17). An increasing volume of data; from Stamey, PCPT and MTOPS trials, points to prostatic volume rather than prostate cancer as the cause of mild elevation of PSA in many men with early cancer (1,18,19). Therefore a high baseline PSA may delay identification of rapid PSA rise. One proposed solution to this problem is use of subtracted PSA values, where baseline PSA is subtracted from all subsequent PSA determinations in calculating doubling time. This is based on a 3-parameter model: PSA = A + BT + CeT where A = baseline PSA from BPH, B = linear increase of PSA from BPH over time (assumed to be minimal), and C = the exponential increase of PSA from CaP over time (20). The concept of correcting for baseline PSA level is also attractive when comparing follow-up data in patients treated definitively with surgery or with radiation. Following radical prostatectomy PSA values usually fall to undetectable levels. After radiation therapy, viable benign prostatic epithelium results in some persistence of PSA. It has been suggested that the nadir PSA be subtracted from the post-radiation PSA level before the PSA-DT is determined (subtraction PSA-DT) (21). This ensures equal PSA-DTs are calculated for patients with the same absolute increase in PSA. Recently a novel method of determining changes in PSA-DT using splines has been described (22). This technique utilizes a best-fitting spline, (i.e. a broken-line approximation) to a graph of log PSA versus time, to estimate PSA-DT before and after treatment. The putative advantages of such a technique are its relative-simplicity and ability to demonstrate statistically significant responses to treatment on an individual patient basis. However, at present, the calculations are too cumbersome for routine clinical use. PSA-DT: A predictor of therapeutic outcome Many attempts have been made to utilize PSA-DT to predict treatment outcome prior to definitive therapy. D’Amico and Hanks found that, following radiation therapy for prostate cancer, PSA-DT was linearly correlated with the interval to clinical relapse following PSA failure (23). They suggest those patients with doubling times > 18 months could be managed expectantly as their cancers were likely to remain latent. Hanks et al. also found that pretreatment PSA-DT significantly correlated with biochemical recurrence (24). Egawa et al. also demonstrated a significant correlation between pre-operative PSA doubling time and biochemical failure post-operatively (25). In this study a doubling time of less than 36 months significantly predicted for extracapsular disease (p=0.02). In contrast, Freedland et al. report a study in which pre-operative PSA-DT did not correlate with adverse pathological findings or biochemical recurrence (12). These differences may reflect the effects of stage migration seen over the last 15 years. PSA-DT and disease progression 13 -15 January 2006, Brussels, Belgium 13 3rd Meeting of the European Society of Oncological Urology (ESOU) Approximately 1/3rd of patients who undergo radical therapy for prostate cancer will experience biochemical recurrence within 10 years of surgery (26). Patients thought to have local recurrence are treated with salvage radiotherapy, whereas those believed to have metastatic disease are treated hormonally. However, the ability to make this crucial distinction accurately is limited. In patients with biochemical failure post RRP, 1/3rd of those with systemic disease will have a PSA < 10ng/ml at the time of diagnosis (27). On this basis Partin recommended bone scan on all patients with post-operative PSA recurrence. However, there is a very low yield from such studies unless the PSA is high or the PSA doubling time is short (28,29). Okotie et al have recently reported that the likelihood of a positive bone-scan, in men with a PSA < 10 ng/ml, increases from 3% if the PSA-DT was greater than 6 months to 26% if the PSA-DT was greater than 6 months (30). Similarly positive CTscans where noted in 24% of men with doubling times less than 6 months vs. 0% if PSADT was greater than 6 months. The probability of, either a positive bone-scan or CTscan increased even further if total PSA was greater than 10ng/ml and PSA-DT less than 6 months. The reported success rates for salvage radiotherapy for clinically localised prostate cancer range from 10-50%. This implies that the majority of these patients harbour unrecognised metastatic disease prior to commencement of treatment, and thus will not benefit from salvage radiation therapy. Stephenson et al have attempted to identify those prostate cancer patients who may benefit from salvage radiotherapy (31). By defining prognostic indicators for these patients, those who are unlikely to benefit may be spared toxicity associated with unsuccessful therapy, or possibly enrolled in randomised trials of novel systemically active agents. In their study, of 501 patients who received salvage radiotherapy for biochemical recurrence, a pre-radiotherapy PSA-DT of 10 months or less was a significant predictor of disease progression. Importantly, a PSA-DT of greater than 10 months also helped identify a subset of men with high-grade disease who were likely to experience a durable response to treatment. PSA-DT and active surveillance There is an increasing concern that patients with good risk prostate cancer are being over-treated. Ideally, those with clinically insignificant prostate cancer should be managed with surveillance. The challenge is to correctly identify such patients, and avoid undertreatment in those with a more aggressive biological phenotype. The key to such strategies is regular observation, so those patients who manifest more aggressive disease are identified when curative treatment is still feasible. Various criteria to identify patients with aggressive disease have been proposed, however to date none of these have been validated (32). Insofar as the PSA kinetics reflect tumor growth, a rapid PSADT in a patient on a watchful waiting protocol likely reflects a more aggressive phenotype. A number of studies have explored the utility of PSA-DT in such a setting. Klotz et al have analysed the distribution of PSA doubling times in a large prospective phase 2 cohort of good risk patients on surveillance (33). The median PSA DT in this group was 7.0 years. Forty two percent of patients had a PSA DT > 10 years. In contrast, 22% had a PSA DT of < 3 years. This group is thought to be at high risk for progression, and was treated radically. At 8 years, this cohort has experienced less than a 1% prostate cancer mortality rate, suggesting that this approach is feasible and safe. McClaren at al demonstrated that PSADT was significantly lower in patients with progressive disease (p<0.001) and strongly correlated with time to treatment (p=0.0001) (34). This study concluded that PSA-DT rather than histopathologic criteria of the tumour were the most important indicator of disease activity. 13 -15 January 2006, Brussels, Belgium 14 3rd Meeting of the European Society of Oncological Urology (ESOU) Stephenson et al have shown that a PSA-DT of less than 120 months correlated with disease progression on DRE and on repeat biopsy (35). The limitation of this parameter is lack of specificity; a cut-off of 120 months will identify 60% of men as having ‘aggressive disease’. Based on well-established incidence to mortality ratios, this is considerably higher than the proportion of patients in this group who are likely to require treatment. El-Geneidy et al have demonstrated that a PSA-DT < 3 years was a significant predictor of intervention on multivariate analysis (36). Meg et al found that amongst patients in the CaPSURE database the mean PSA increase in those progressing to treatment was 7.2ng/ml (37). Treatment was instigated at a median of 1.7 years from diagnosis in these patients. In contrast over the same time period the mean PSA decreased 0.4ng/ml in those patients electing to continue with watchful waiting (p<0.001). These data confirm the ability of PSA-DT in conjunction with other indicators of disease progression (PSA velocity, clinical and pathological changes) to identify patients who require definitive therapy amongst watchful-waiting cohorts. A number of potential pit-falls exist when analyzing PSA-DT data from patients on active surveillance protocols. Significant variability in PSA-DT has been demonstrated in such groups (33). Surveillance patients should have PSA estimations performed on a three monthly basis and therefore have a relatively large number of data points available for analysis. Given the short-term physiological variability in PSA measurements it is not surprising such variability exists. Therefore the interval on which determination of PSA DT is based must be sufficiently long (6-12 months) to avoid decisions based on random variation in PSA (38). PSA-DT AS A MARKER OF CANCER SPECIFIC MORTALITY Patients with a short PSA-DT (<12 months) following radiation therapy have almost identical estimates of prostate-cancer specific and all-cause mortality (39). In other words almost all deaths in this subset of patients were secondary to prostate cancer. This implies therefore that such patients should be considered candidates for adjuvant trials to prevent an otherwise inevitable prostate cancer related death. In keeping with this data Sandler at al have demonstrated in patients with biochemical recurrence following XRT, that 5 year prostate cancer specific mortality rates decrease from 52% to 10% in patients with a PSA doubling time <12 months compared with greater than 1 year (p=0.007) (40). It is possible to stratify prostate cancer specific mortality into high or low risk categories on the basis of PSA-DT following local therapy. In a retrospective analysis of the CaPSURE and CPDR databases, the risk of prostate cancer specific mortality was 20 times greater in men with a PSA-DT < 3 months (high-risk, median survival 6 months) compared to men with a doubling time >18 months (median survival > 10 years) (39). Utility of PSA-DT in clinical trials If a short PSA-DT is a predictor of negative outcome then a prolonged PSA-DT implies a prostate cancer specific survival advantage. PSA doubling time may also predict response to secondary hormonal intervention in men with androgen independent prostate cancer (AIPC). Approximately one third of men with AIPC experience a clinical response to secondary hormonal manipulation. The ability to predict response could avoid the toxicity associated with such treatment in those patients who are unlikely to respond. Shulman et al have analysed pre-treatment variables in patients with AIPC to determine the effect on PSA response following instigation of maximum androgen blockade (41). PSA-DT was the only significant predictor of response, (12.7 months in responders versus 7.5 months in non-responders (p=0.037). The study also addresses 13 -15 January 2006, Brussels, Belgium 15 3rd Meeting of the European Society of Oncological Urology (ESOU) an interesting question as to which patients may benefit from secondary hormonal manipulation and which from cytotoxic chemotherapy. PSA-DT also has a role in determining the timing of androgen deprivation in patients with PSA progression after surgery. Moul has reported the effect of early vs delayed hormonal therapy on disease free survival in patients with PSA only recurrence following RRP (42). 355 men received early hormonal therapy (hormonal therapy instigated on the basis of PSA recurrence alone with no clinical evidence of metastatic disease). 997 men were either treated hormonally at the time of diagnosis of systemic disease or, to date have not been treated hormonally. Strikingly, timing of therapy had no impact overall in the time to androgen independent progression. However, in those patients with a rapid PSA-DT (<12 months) or high-grade disease, early hormonal therapy (for PSA < 10) was associated with a delay in the time to androgen independent progression. . This important study suggests that patients with PSA recurrence should only be treated if their PSA DT is < 1 year, or they have Gleason 8-10 cancer; otherwise, ADT should be withheld until clinical progression or a rapid PSA DT develops.. It also supports a PSA threshold of 5-10 for initiating treatment in the high-risk patients. Clinical trials of new mechanistic agents in prostate cancer face a number of difficulties. The assessment of novel agents utilised in solid organ cancer therapy is based on the radiological and pathological response of indicator lesions. Men with biochemical recurrence following definitive therapy frequently have non-measurable disease. Secondly the use of time to progression and survival as end points pose problems given the prolonged natural history and variable clinical course of the disease. PSA-DT appears to be sufficiently robust as a surrogate marker of prostate cancer survival that it may serve as a valid end point in trials of patients with hormone-refractory disease (43). Conclusions The limitations of PSA in screening and early detection, predicting outcome, and identifying patients at risk for death after radical therapy are largely based on the use of a single PSA determination. In contrast, increasing evidence supports the use of PSA kinetics (velocity, doubling time, acceleration, etc.) as a powerful indicator of tumour biology. Preoperative PSA-V appears to be one of the most important predictors of death in patients with localised prostate cancer. It can be used as a means to stratify high-risk patients who may benefit from adjuvant therapy from good-risk patients who are likely to require standard therapy only. PSA-V and DT are useful in monitoring disease recurrence and progression following failure of definitive therapy. Doubling time in particular has the ability to identify patients at high risk of rapidly progressive disease. This information should guide treatment decisions about radiation vs. ADT for biochemical recurrence, the timing of ADT, and the use of second line androgen deprivation. The protracted natural history of prostate cancer necessitates very prolonged data gathering in clinical trials. Proof of a survival advantage associated with novel treatment is therefore very difficult to establish, particularly given the advanced age of many prostate cancer patients to begin with. Determination of PSA kinetics in such a setting may allow for a more rapid and meaningful evaluation of novel therapeutic strategies. 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Klotz, Division of Urology, Sunnybrook and Women’s College Health Sciences Centre, 2075 Bayview Ave, Toronto, Ontario, M4N 3M5, Canada. email:[email protected] 13 -15 January 2006, Brussels, Belgium 19 3rd Meeting of the European Society of Oncological Urology (ESOU) PSA MARKERS IN PROSTATE CANCER DETECTION H. Özen, Ankara Turkey Serum prostate specific antigen testing has had a profound effect on prostate cancer detection, prognostication and assessment of outcomes of care. Failure to acknowledge its impact across all areas underestimates its current value. Its value in the early detection of prostate cancer has been called into question because of two issues. First, many men with normal PSA values may harbor prostate cancer. Second, and related to this phenomenon, is the fact that serum PSA may not correlate with prostate cancer volume in heavily screened patient populations. The first issue was dramatically illustrated in the analysis of the Prostate Cancer Prevention Trial (PCPT) published in 2004. Of 2950 men who underwent end of study biopsy and have serum PSA values < 4.0 ng/ml, 449 or 15.2% had prostate cancer. Many have used this information to argue cogently for lowering the PSA threshold for biopsy. This study does highlight that a normal PSA does not exclude cancer and that better markers are needed, especially in the low PSA range. Stamey and colleagues have shown that serum PSA no longer correlates with prostate cancer volume, but more strongly with total prostate volume in the contemporary time period. Others who show that serum PSA correlates more strongly with cancer volume than total prostate volume have challenged this notion. However, the phenomenon is a product of widespread screening and re-screening. The correlation of PSA with cancer volume is clearly stronger at first PSA assessment and less so over time in those undergoing re-screening and biopsy. Serum PSA or One of Its Isoforms? Whether one should use total PSA or one of its derivatives is also a matter of debate. Some use such derivatives, such as percent-free PSA, to improve test specificity in those who may be candidates for a repeat biopsy or who have serum PSA values below 4 ng/ml. The biochemistry of PSA isoforms present in the bloodstream has been studied extensively. Once PSA gains access to the systemic circulation, the majority form complexes with prostate inhibitors, which are abundant in the serum. Numerous reports have showed that free-to-total PSA (f/tPSA) ratio is relatively lower in men with prostate cancer compared to men with benign disease. A higher proportion of complexed PSA (cPSA) is found in the serum of men with prostate cancer and cPSA determination has been recommended to improve the specificity of total PSA. Ankara study demonstrated that the use of cPSA as a single test provided specificity over PSA and f/t PSA in PSA ranges between 2-20 ng/ml. In addition, cPSA volume related parameters further improved the ability of cPSA in early prostate cancer detection, especially in small prostates (Total volume<45cc and TZ volume<26cc). These findings indicate that cPSA might be a better initial test than PSA for prostate cancer detection and measurement of cPSA alone obviates the need for additional fPSA testing for further urological evaluation. More recently, a meta-analysis of PSA isoforms for the detection of PCa in men with a PSA level of 2-10 ng/ml was published. This study has shown that the diagnostic performance of f/tPSA and cPSA is equivalent in both 2-4 and 4-10 ng/ml tPSA ranges, whilst the performance of the f/tPSA test in the 4-10 ng/ml range is significantly superior to that in the 2-4 ng/ml range. Recently, pro forms of PSA have been reported to be more cancer specific markers of prostate cancer than total PSA and they also may preferentially detect the more aggressive forms of this disease. Catalona et al evaluated the performance of serum precursor forms of PSA (pro PSA) in improving cancer detection when compared with free PSA and complexed PSA in men with various PSA ranges from 2-10. 1091 men who had undergone blood testing and prostate biopsy in two cancer screening sites were studied. In this range, with 90% sensitivity, %pro PSA (proPSA/free PSA) spared 19% of 13 -15 January 2006, Brussels, Belgium 20 3rd Meeting of the European Society of Oncological Urology (ESOU) unnecessary biopsies as compared to 10% for free PSA alone and 11% for complexed PSA alone. Similar results were obtained for other PSA ranges from 2-20 ng/ml. In addition to the use of PSA/PSA isoforms used singly or together, PSA measurements have been used with other molecular tests to improve prostate cancer detection, especially in the ranges where PSA performs poorly as a screening test, namely 4-10 ng/ml and <4 ng/ml. 1. 2. 3. 4. 5. 6. REFERENCES Stamey TA et al: The prostate specific antigen era in the United States is over for prostate cancer: what happened in the last 20 years? J Urol, 172: 1297, 2004. Punglia RS et al: Effect of verification bias on screening for prostate cancer by measurement of prostate specific antigen. N Engl J Med, 349: 335, 2003. Djavan B et al: Complexed prostate specific antigen, complexed prostate specific antigen density of total and transition zone, complexed/total prostate specific antigen ratio, free to total prostate specific antigen ratio, density of total and transition zone prostate specific antigen: results of the prospective multicenter European trial. Urology, 60: 4, 2002. Sözen S et al: Complexed prostate specific antigen density is better than the other PSA derivatives for detection of prostate cancer in men with total PSA between 2.5 and 20 ng/ml: Results of a prospective multicenter study. Eur Urol, 47, 302, 2005. Rodam AW et al: Use of Prostate – Specific Antigen (PSA) Isoforms fort he detection of Prostate Cancer in men with PSA level of 2-10 ng/ml: systematic review and meta-analysis. Eur Urol, 48, 386, 2005. Catalona WJ et al: Serum pro prostate specific antigen improves cancer detection compared to free and complexed prostate specific antigen in men with prostate specific antigen 2 to 4 ng/ml. J Urol, 170: 2181, 2003. 13 -15 January 2006, Brussels, Belgium 21 3rd Meeting of the European Society of Oncological Urology (ESOU) ACTIVE SURVEILLANCE WITH SELECTIVE DELAYED INTERVENTION FOR FAVOURABLE RISK PROSTATE CANCER L. Klotz Toronto, Canada R.Nam SUMMARY This review summarizes the case for active surveillance for ‘favorable-risk’ prostate cancer with selective delayed intervention for rapid biochemical progression, assessed by rising prostate-specific antigen (PSA) levels, or grade progression. The results of a large phase II trial using this approach are also reviewed. A prospective phase II study of active surveillance with selective delayed intervention was initiated in 1995. Patients were managed initially with surveillance; those who had a PSA doubling time (PSADT) of 2 years or less, or grade progression on rebiopsy were offered radical intervention. The remaining patients were closely monitored. The cohort consists of 299 patients with good-risk prostate cancer, or intermediate-risk prostate cancer in men over 70 years of age. The median PSADT was 7 years, 42% had a PSADT >10 years. The majority of patients remain on surveillance. At 8 years, overall actuarial survival is 85%, and disease-specific survival is 99%. To date, this study has shown that virtually all men with favorable -risk’ prostate cancer managed in this fashion will die of unrelated causes. The approach of active surveillance with selective delayed intervention based on PSADT and repeat biopsy represents a practical compromise between radical therapy for all patients, (which results in overtreatment for patients with indolent disease), and watchful waiting with palliative therapy only, (which results in undertreatment for those with aggressive disease). NOTES 13 -15 January 2006, Brussels, Belgium 22