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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].
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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
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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
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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
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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 + CeT
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
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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.
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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
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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.
Analysis of PSA kinetics should play a major role in the management of localised and
advanced prostate cancer.
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antigen doubling time as a surrogate end point for prostate cancer specific mortality
following radical prostatectomy or radiation therapy. J Urol. 2004; 172(5 Pt 2): S42-6.
Correspondence. L. Klotz, Division of Urology, Sunnybrook and Women’s College
Health Sciences Centre, 2075 Bayview Ave, Toronto, Ontario, M4N 3M5, Canada.
email:[email protected]
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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
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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.
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2.
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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
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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
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