R Minervini

R Pagni

C Mariani

A Morelli

G Morelli

MD Andrea Minervini
email: andreamine@libero.it

Ureteroenteric Refluxing

Anastomoses

Effects on renal function of obstructive and nonobstructive dilatation of the upper urinary tract in ileal neobladders with refluxing ureteroenteric anastomoses

Keywords: orthotopic ileal neobbladder, urinary diversion, direct anastomosis, reflux, anastomotic stricture, renal function

come

Effects on renal function of obstructive and nonobstructive dilatation of the upper urinary tract in ileal neobladders with refluxing ureteroenteric anastomoses

INTRODUCTION

Radical cystectomy is the treatment of choice for muscle-invasive bladder cancer [START_REF] Oosterlinck | Guidelines on bladder cancer[END_REF] and even if recent reports have shown that patients with a neobladder enjoy marginal quality of life advantages over those with an ileal conduit 2-4 , orthotopic bladder reconstruction remains the best option for patients undergoing cystectomy [START_REF] Hautmann | Urinary diversion: ileal conduit to neobladder[END_REF][START_REF] Studer | Twenty years experience with an ileal orthotopic low pressure bladder substitute-lesson to be learned[END_REF] .

In patients with a neobladder, the preservation of renal function is the ultimate goal of successful treatment [START_REF] Minervini | Evaluation of renal function and upper urinary tract morphology in the ileal orthotopic neobladder with no antireflux mechanism[END_REF] and can be influenced by several factors including ureteral obstruction, urinary tract infection (UTI) and reflux [START_REF] Jr | Incidence and significance of positive urine cultures in patients with an orthotopic neobladder[END_REF][START_REF] Okur | The role of infection and free oxygen radical damage in reflux nephropathy: an experimental study[END_REF][START_REF] Ransley | Reflux and renal scarring[END_REF] .

Dilatation of the upper urinary tract is the major concern in ureteroileal anastomosis [START_REF] Stein | Complications of the afferent antireflux valve mechanism in the Koch ileal reservoir[END_REF] and can be caused by strictures of the ureter and reflux [START_REF] Minervini | Evaluation of renal function and upper urinary tract morphology in the ileal orthotopic neobladder with no antireflux mechanism[END_REF] .

The general question is whether a refluxing or nonrefluxing technique should be chosen.

Proponents of nonrefluxing techniques cite the harmful effects on renal function of recurrent pyelonephritis caused by reflux [START_REF] Okur | The role of infection and free oxygen radical damage in reflux nephropathy: an experimental study[END_REF][START_REF] Ransley | Reflux and renal scarring[END_REF] and bacteriuria [START_REF] Jr | Incidence and significance of positive urine cultures in patients with an orthotopic neobladder[END_REF] and the potential benefit in patients undergoing intermittent catheterization. Nevertheless, the danger to renal function caused by anastomotic stricture that occurs at a higher rate after an antirefluxing technique than after direct anastomosis is well documented [START_REF] Hautmann | Urinary diversion: ileal conduit to neobladder[END_REF][START_REF] Pantuck | Ureteroenteric anastomosis in continent urinary diversion: long-term results and complications of direct versus nonrefluxing techniques[END_REF][START_REF] Ayman | Evaluation of direct versus non refluxing technique and functional results in orthotopic Y ileal neobladder after 12 years after follow up[END_REF] and it is reflected by the number of different antireflux mechanisms developed during the years, such as afferent nipple valves 14 , the Le Duc technique [START_REF] Duc | An original antireflux ureteroileal implantation technique. Long term follow up[END_REF] , split-cuff ureteral nipples [START_REF] Sagalowsky | Early results with split-cuff nipple ureteral reimplants in urinary diversion[END_REF] , the Abol-Enein and Ghoneim technique [START_REF] Abol-Enein | A novel uretero-ileal reimplantation technique: the serous lined extramural tunnel. A preliminary report[END_REF] , the T pouch tecnique [START_REF] Stein | The T-pouch: an orthotopic ileal neobladder incorporating a serosal lined ileal antireflux technique[END_REF] and an afferent ileal tubular segment [START_REF] Studer | Experience in 100 patients an ileal low pressure bladder substitute combined with an afferent tubular isoperistaltic segment[END_REF] ; however, the multiplicity of these techniques suggests that an ideal solution has not yet been found.

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On the contrary, using a direct anastomosis, anastomotic strictures occur at a significantly lower rate than after an antireflux technique [START_REF] Hautmann | Urinary diversion: ileal conduit to neobladder[END_REF] , but ureteral reflux might potentially endanger kidney function on the long term follow up [START_REF] Ransley | Reflux and renal scarring[END_REF] .

In this study we investigated the incidence of obstructive and nonobstructive dilatation of the upper urinary tract, caused by ureterointestinal stricture and reflux, respectively, and their impact on split renal function in the long term in patients who had a low pressure ileal neobladder constructed using refluxing ureterointestinal anastomoses.

MATERIALS AND METHODS

Patients Population

A prospective derived database of patients undergoing ileal neobladder for bladder cancer was retrospectively analyzed. Between May 1996 and March 2007, 110 consecutive men (mean age 63.8 years, range 45-79) underwent radical cystectomy and orthotopic neobladder formation.

Inclusion criteria for continent urinary diversion were normal renal function, absence of gastrointestinal disease and absence of tumor at the prostatic urethra. Preoperative evaluation included serum creatinine, ultrasonography and computerized tomography of the abdomen and pelvis. Mean (range) preoperative serum creatinine was 0.99 mg/dl (0.7-1.5, normal 0.7-1.4) (87.5 µmol/L, range 62-133, normal 62-124).

Surgical Technique

In all cases, the W-shaped ileal neobladder and ureteral anastomoses on a short afferent limb were done according to our previously described standard technique using 45 to 47 cm of ileum [START_REF] Minervini | Evaluation of renal function and upper urinary tract morphology in the ileal orthotopic neobladder with no antireflux mechanism[END_REF][START_REF] Minervini | Functional evaluation of different ileal neobladders and ureteral reimplantation techniques[END_REF] . The distal 40 cm were detubularized on a silicone tube and oriented into a "W" shape, the proximal 5 to 7 cm left intact for anastomosis with the ureters. The ureters were spatulated and implanted to the ileal chimney using the Nesbit nontunneled end-to-side ureteroileal anastomosis with 2 running 5-0 absorbable sutures.

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Evaluation of renal function during follow up

The patients were routinely examined every 6 months for the first 3 years and yearly thereafter. At every follow up visit the patients underwent serum creatinine, urine culture, abdominal CT scan or ultrasonography, and, in case of dilatation of the upper urinary tract at the imaging study, 99mTc- DTPA renal scintigraphy with a Foley catheter in the neobladder was requested to evaluate total and split GFR and to define the cause of the dilatation: obstructive, caused by anastomotic stricture or nonobstructive, caused by reflux.

The dilatation was considered obstructive if appearance of the radioisotope in the pelvicaliceal system was delayed, if there was retention of activity in the dilated collecting system over time and if T½ of the time-activity curve was greater than 20 minutes after intravenous administration of furosemide. Nonobstructive dilatation was assumed if the collecting system was dilated and the T½ of the time-activity curve was less than 10 minutes after furosemide injection.

Total and split renal function of patients with obstructive and nonobstructive dilatation was evaluated by measurements of plasma creatinine and GFR. Plasma creatinine was measured with the standard autoanalyzer technique. Standard 99mTc-DTPA renal scintigraphy and Gates' method were used to calculate GFR. GFR values measured as the renal clearance of 99mTc-DTPA are reported with reference to the standard body surface area of 1.73 m 2 21,22 .

Clean catch urinalysis and urine cultures were done according to standard sterile procedures. UTI was defined as a urine culture showing greater than 10,000 cfu bacteria plus suprapubic pain or greater than 100,000 cfu bacteria with or without symptoms. Urosepsis was defined as greater than 100,000 cfu bacteria in the urine plus evidence of a positive blood culture [START_REF] Jr | Incidence and significance of positive urine cultures in patients with an orthotopic neobladder[END_REF] .

The final evaluation of patients status was in March 2008. The mean follow up was 65 months (range 12 to 141 ). A total of 40 patients died during follow up, 32 of bladder carcinoma and eight of causes independent from bladder tumor.

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RESULTS

Of the 110 patients, two died in the perioperative period and three were lost to follow-up. Of the 105 patients (210 renoureteral units), two had resection of the distal ureter and reimplantation for recurrent disease at 50 and 62 months after surgery and two had nephroureterectomy for upper urinary tract transitional cell carcinoma at 45 and 58 months after surgery. Therefore this study is based on a series of 206 renoureteral units (105 patients) and of those 20 units (17 patients) showed a dilatation detected during follow up and were further investigated.

Obstructive dilatation

Overall, in our series, seven renoureteral units had anastomotic stricture (Table 1) and of those, three had symptomatic anastomotic stricture detected at 2, 4 and 8 months after surgery (three renal units). These patients were treated with surgical reimplantation. Four patients had anastomotic stricture detected as asymptomatic dilatation of the upper urinary tract at 6, 12, 24 and 24 months after surgery (four renal units). The split GFR in these four patients was 45, 40, 21 and 26.3 ml/minute respectively and only patients with split GFR of 45 and 40 ml/minute were treated with surgical reimplantation. The nuclear renography at 6 months after diagnosis showed a GFR of 43.2 and 38.2 ml/minute, respectively, in patients treated with surgical reimplantation. The resolution of the anastomotic stricture was confirmed at the last follow up visit at 56 and 74 months after surgery with a split GFR of 39.2 and 34.8 ml/minute, respectively. There was a decrease to 14.2 and 16.3 ml/minute at the last nuclear renography performed 36 and 48 months after diagnosis in patients that were not treated.

Nonobstructive dilatation

The renal scan revealed nonobstructive dilatation of the upper urinary tract in ten patients (Table 2).

The dilatation was bilateral in three patients with recurrent UTIs and urosepsis. The split GFR in these patients at diagnosis was 22/25, 31.2/33.2 and 27.6/28.3 ml/minute, and showed a further The dilatation was unilateral and moderate in the remaining seven patients, with sterile urine or one positive urinalysis during follow up. These patients showed a preserved split GFR symmetrical with the nondilated renal unit, with a mean of 47.3 ml/minute at diagnosis that did not showed a significant reduction during follow up after a further mean (range) follow up of 44 (36-51) months (Table 2).

DISCUSSION

Reflux prevention in orthotopic bladder substitutes remains a controversial issue and although excellent long term results have been described using refluxing anastomoses, many surgeons continue to perform antireflux procedures [START_REF] Skinner | Does reflux in orthotopic diversion Matter? A randomized prospective comparison of the Studer and T-pouch ileal neobladders[END_REF] .

The aim of the present study was to investigate the incidence of obstructive and nonobstructive dilatation of the upper urinary tract and their impact on split renal function on the long term in patients who had a low pressure ileal neobladder constructed using refluxing ureterointestinal anastomoses. Unfortunately our patients did not have a preoperative renal scan and this can be considered the main bias of this study but all patients had a thorough preoperative evaluation that included serum creatinine, ultrasonography and computerized tomography and all the 17 patient showing postoperative upper tract dilatation either due to stricture or reflux presented a normal morphology of the upper urinary tract before surgery associated with normal serum creatinine.

Anastomotic stricture: refluxing vs nonrefluxing techniques

All ureterointestinal anastomoses, whether antireflux or not, have an inherent risk of stricture with consequent ureteral obstruction and, thus, potential renal impairment. However, this risk appears, to be appreciatively higher after an antireflux technique than after direct anastomosis, irrespective of the anastomosis technique and the segment of bowel used [START_REF] Stein | Complications of the afferent antireflux valve mechanism in the Koch ileal reservoir[END_REF][START_REF] Yang | Long term effects of ileal conduit urinary diversion on upper urinary tract in bladder cancer[END_REF][START_REF] Burkhard | Continent urinary diversion[END_REF] with a reported stricture rate of 1-4% for the direct anastomosis and of 9.5-20% for the different antireflux techniques described in

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the literature [START_REF] Hautmann | Urinary diversion: ileal conduit to neobladder[END_REF][START_REF] Minervini | Evaluation of renal function and upper urinary tract morphology in the ileal orthotopic neobladder with no antireflux mechanism[END_REF][START_REF] Pantuck | Ureteroenteric anastomosis in continent urinary diversion: long-term results and complications of direct versus nonrefluxing techniques[END_REF][START_REF] Roth | Does the success of ureterointestinal implantation in orthotopic bladder substitution depend more on surgeon level of experience or choice of technique? 4[END_REF]27 . Better results were reported by Osman et al. with a 5.1% obstruction rate using the serous lined extramural tunnel technique 28 , and by Skinner with the ileal T pouch neobladder [START_REF] Stein | The T-pouch: an orthotopic ileal neobladder incorporating a serosal lined ileal antireflux technique[END_REF] . However, the T mechanism is not easy to construct, time-consuming and yet to be widely adopted.

Anastomotic stricture: long-term effects on renal function and treatment options

In our series, using a Nesbit nontunneled end-to-side ureteroileal anastomosis the stricture rate was 3.4% and in three over seven cases the strictures caused acute symptoms such as flank pain and fever. All symptomatic strictures occurred within the first 8 months after surgery and all were treated with open reimplantation. Others proposed the endourological treatment that consists in balloon dilatation or incision of the stricture due to its lower morbidity in comparison to the open surgical treatment 29 , but we, and others consider the open surgical revision as the preferred method for its significantly higher success rate [START_REF] Pantuck | Ureteroenteric anastomosis in continent urinary diversion: long-term results and complications of direct versus nonrefluxing techniques[END_REF] .

Another possible presentation of anastomotic strictures is in asymptomatic patients during follow up imaging showing unilateral hydronephrosis possibly associated with signs and symptoms of UTIs, pyelonephritis and increased serum creatinine. In our series, four anastomotic strictures were diagnosed during follow up in asymptomatic patients. We opted for open surgical treatment in two cases with a preserved split GFR at renal scintigraphy while decided for a close follow up in the other two patients due to the very poor split renal function of the obstructed unit with a preserved contralateral kidney function that in our view lowered the advantages of the surgical correction associated with all the possible complications of this type of surgery. Nevertheless, in these two patients, the last nuclear renography performed 3 and 4 years after diagnosis showed a further significant decrease of the split GFR. Therefore, we believe that all strictures, once detected, should be treated surgically with reimplantation because also asymptomatic strictures invariably lead to deterioration of kidney function during follow up.

Long-term effects of reflux on renal function

While the danger to renal function caused by anastomotic stricture is well documented in orthotopic

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neobladders, the benefits of reflux prevention are only clear for the continent cutaneous pouch requiring intermittent catheterization and for ureterosigmoidostomy, both usually showing high reservoir pressures and bacteriuria 30 . However, in the orthotopic neobladder, which is a low pressure reservoir with no major coordinated contractions and either with sterile urine or with asymptomatic bacterial colonization, the benefits related to reflux prevention are not well documented [START_REF] Burkhard | Continent urinary diversion[END_REF] .

All literature data suggest that even if present, reflux per se, does not provoke renal impairment unless infected urine is present. Indeed, most clinical and experimental studies show the important role of UTI together with reflux in the development of reflux nephropathy scars [START_REF] Okur | The role of infection and free oxygen radical damage in reflux nephropathy: an experimental study[END_REF][START_REF] Ransley | Reflux and renal scarring[END_REF][START_REF] Burkhard | Continent urinary diversion[END_REF] .

Moreover, asymptomatic bacterial colonization is not sufficient to cause renal damage but recurrent UTIs are; the latter occurring especially in women with hypercontinence and in men with severe voiding dysfunction [START_REF] Jr | Incidence and significance of positive urine cultures in patients with an orthotopic neobladder[END_REF] . In our series we confirm this assumption. Indeed, of the ten patients with nonobstructive dilatation caused by reflux, only three who had recurrent UTI and urosepsis had a severe reduction of parenchymal uptake during follow up, while the remaining seven patients, with sterile urine or one positive urinalysis during follow up, showed a preserved split GFR symmetrical with the not dilated renal units, that did not showed a significant reduction during follow up.

CONCLUSIONS

The direct, end-to-side Nesbit ureteroenteric anastomosis is a safe and acceptable technique for ureteral reimplatation in low pressure ileal neobladder, it provides excellent long-term results with a low stricture rate. All strictures, once detected, should be treated surgically with reimplatation because even asymptomatic strictures can lead to deterioration of kidney function during follow up.

Reflux per se does not provoke renal impairment unless recurrent UTIs and urosepsis are present. In the latter, a progressive decrease in kidney function is awaited.

  reduction to 15/17, 19/25.2 and 21.1/25.3 ml/ minute at the last nuclear renography performed at 17, 47 and 51 months after surgery.

  UE and Zingg EJ. Ileal orthotopic bladder substitutes. What we have learned from 12 years' experience with 200 patients. Urol Clin North Am 1997; 24: 781-793 28. Osman Y, Abol-Enein H, Nabeeh A, et al. Long-term results of a prospective randomized study comparing two different antireflux techniques in orthotopic bladder substitution. Eur Urol 2004; 45: 82-86 29. Kramolowsky EV, Clayman RV, Weyman PJ. Management of ureterointestinal anastomotic strictures: comparison of open surgical and endourological repair.J Urol1988;139(6):1195-8. 30. Hautmann R.E., Abol-enein H., Afez K., et al. Urinary diversion. Urology 2007 ; 69 (1A):17-49 M A N U S C R I P T A C C E P T E D M A N U S C R I P T A C C E P T E D ARTICLE IN PRESS

  Tab.1: GFR and characteristics of the 7 patients with obstructive dilatation of the upper urinary tract.Tab. 2: GFR and characteristics of the 10 patients with non-obstructive dilatation of the upper urinary tract.

		ARTICLE IN PRESS
	1 2 3 4 5 6 7 8	GFR at diagnosis (ml/minute) total right left ------8 1.42 [125.5] -Diagnosi s Creat (mg/dl) [µmol/L] (months) at diagnosis 2 1.5 [133] 4 1.35 [119] --6 1.2 [106] 97 45 52 90.5 39.2 51.3 GFR at last follow up (ml/minute) total right left 90.6 50.2 40.4 96.4 51.3 45.1 102.3 46 56.3 12 1.23 [109] 98 58 40 93.8 59 34.8 6 Asymptomatic 24 Obstructive Dilatation 1 Symptomatic 2 Symptomatic 3 Symptomatic 4 Asymptomatic 5 Asymptomatic 1.36 [120] 83 62 21 75.6 61.4 14.2 7 Asymptomatic 24 1.45 [128] 84.3 58 26.3 72.3 56 16.3 GFR at diagnosis (ml/minute) GFR at last follow up (ml/minute) Unobstructive Dilatation Diagnosis (months) Creat (mg/dl) [µmol/L] at diagnosis total right left total right left bilateral Recurrent UTI 21 1.28 [113.5] 47 22 25 32 15 17 bilateral Recurrent UTI 22 0.8 [71] 64.4 31.2 33.2 44.2 19 25.2 bilateral Recurrent UTI 25 1.25 [110.5] 55.9 27.6 28.3 46.4 21.1 25.3 Monolateral No UTI 42 1.07 [95] 106.5 53.7 52.8 102.6 52 50.6 Monolateral No UTI 90 1.31 [116] 84.6 45 39.6 82.4 46 36.4 Monolateral No UTI 83 1.12 [99] 106.5 53.5 53 103.1 53 50.1 A N U S C R I P T Follow up (months) 27 62 35 56 74 36 48 Follow up (months) 17 47 51 36 39 46 Monolateral No UTI 27 1.14 [101] 106.8 53 53.8 103.8 53 50.8 48 M Monolateral 52 1.27 [112] 106.2 52.9 53.3 102.8 50.1 52.7 44
		No UTI
	9 10	Monolateral No UTI No UTI A C C E P T E D 48 1.35 [119] 85.1 43.8 41.3 81.9 43.2 38.7 Monolateral 31 1.4 [124] 80.7 38.2 42.5 76.9 35.4 41.5	42 51
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CONFLICT OF INTEREST

We confirm that: 2. All have read and approved the final manuscript.

3. All have no commercial relationship such as consultancies, stock ownership or other equity interests, patents received and/or pending, or any commercial relationship which might be in any way considered related to the abovementioned submitted article.


Parvez

M.D Renata Soumarova
email: renata.soumarova@radioterapie.cz

M Skrovina

J Bartos

J Gruna

A Wendrinski

S Czudek

R Kycina

J Parvez

Neoadjuvant chemoradiotherapy with capecitabine followed by laparoscopic resection in locally advanced tumors of middle and low rectum -toxicity and complications of the treatment

Keywords:

Neoadjuvant chemoradiotherapy with capecitabine followed by laparoscopic resection in locally advanced tumors of middle and low rectum-toxicity and complications of the treatment

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Abstract

Aims:

The aim of this prospective study is to elucidate feasibility of protocol of neodjuvant concomitant radio chemotherapy with capecitabine and long course radiotherapy with subsequent laparoscopic rectal resection. We assessed treatment toxicity, downstaging rate, pathological response to the neoadjuvant treatment, surgery complications, rate of conversions and sphincter-preserving surgical procedures, and intraoperative and early postoperative complications too.

Methods:

We acquired data of 78 patients from 1 January 2005 to 31 December 2007 with a locally advanced rectal cancer in our study. All patients were indicated for the neoadjuvant concomitant chemoradiotherapy due to locally advanced tumor (T3 or T4) or lymph nodes involvement suspicion (N+). Both radiotherapy (to pelvic region) and chemotherapy (capecitabine) were administered. Rectal tumors were localized within 12cm from the anocutaneous verge. The average follow-up time was 23.9 months.

Results:

All patients completed their treatment according to the planned regimen and dose. The surgery was performed laparoscopicaly within 4-8 weeks following the concomitant chemoradiotherapy -in 17% cases was converted into conventional surgery. Downstaging was achieved in 69% of patients, pathological complete response in 10 %, histologically negative lymph nodes were documented in 58% of patients. Grade 3 toxicity of the concomitant chemoradiotherapy was present in 3%; grade 2 in 29% of patients, particularly skin and gastrointestinal form. Intraoperative and early postoperative complications of the surgery were 18%. Reoperation was needed in 5% cases.

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Introduction

Curative radical surgery is essential treatment of the localized rectal tumors. In the locally advanced tumors (T3, T4 or N+) the surgery is combined with preoperative radiotherapy (RT), which leads to better local control of the disease and to improved survival compared with surgery alone [START_REF] Camma | Preoperative radiotherapy for resectable rectal cancer: A meta-analysis[END_REF][START_REF] Glimelius | Radiotherapy in addition to radical surgery in rectal cancer: Evidence for a dose-response effect favoring preoperative treatment[END_REF]. Randomized trials have demonstrated, that the outcomes of concomitant chemoradiotherapy (CHT/RT) are superior to the radiotherapy alone (3). The EORTC phase III trial compared radiotherapy alone with radiotherapy combined with chemotherapy (CHT) consisting of administration of 5-fluorouracil and leucovorine (FUFA) as a bolus in weeks 1 and 5. In the CHT arm was the rate of pathological complete response significantly higher; it is very important for the prognosis of the patient (4).

The primary endpoint of the neoadjuvant concomitant chemoradiotherapy is overall survival improvement but an important secondary aim is to reduce the size of the tumor (downstaging) but to improve the local disease control too. Highly discussed benefit of this treatment is the increasing of sphincter-preserving surgeries in more distally located tumors too. In some trials this benefit was statistically significant; in other trials it was not confirmed. Major German trial (CAO/ARO/AIO-94) compared the use of concomitant CHT/RT before the surgery and after the surgery [START_REF] Sauer | German Rectal Cancer Study Group, Preoperative versus postoperative chemoradiotherapy for rectal cancer[END_REF]. Sphincter-preserving surgery following preoperative administration was successfully performed in 39% vs. 19% in after CHT/RT surgery group, late stenosis of the anastomosis occurred in 3% vs. 9%, local recurrence occurred in 7% vs. 11%. Grade 3 and 4 acute toxicity was lower in neoadjuvant concomitant CHT/RT group (27% vs. 40%), late toxicity too (14% vs. 24%). However, distant dissemination was comparable in both arms (34% vs. 36%) as well as overall survival (76% vs. 74%).

Continual administration of 5-fluorouracil is more favorable over the bolus administration as for the toxicity, but the handicap is a need of hospitalization and central venous catheter insertion, both with negative influence on the quality of life of the oncological patients [START_REF] Rich | Preoperative infusional chemoradiation therapy for stage T3 rectal cancer[END_REF].

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Capecitabine (Xeloda; Hoffmann-LaRoche, Inc., Nutley, NJ) imitates the continual administration of 5-FU. According to phase I study the recommended capecitabine dose 825 mg/m 2 administering twice daily was determined for concomitant administration with radiotherapy [START_REF] Ngan | A phase I trial of preoperative radiotherapy and capecitabine for locally advanced, potentially resectable rectal cancer[END_REF]. Phase II studies have confirmed good tolerance and efficacy in patients with locally advanced rectal cancer [START_REF] Dupuis | Capecitabine (X) chemoradiation (CRT) in the preoperative treatment of patients (pts) with rectal adenocarcinomas: a phase II GERCOR trial. Abstract 3538[END_REF] Laparoscopic surgery is alternative to the open surgical procedure which comply all criteria for oncological radicality [START_REF] Feliciotti | Results of laparoscopic vs open resections for colon cancer in patients with a minimum follow-up of 3 years[END_REF][START_REF] Jacob | Laparoscopic colectomy for colon adenocarcinoma[END_REF].

Material and methods

All patients were completely examined and underwent all staging procedures, including CT, transrectal sonography and MRI. Blood analysis, including tumor marker analysis was performed as a standard part of the examination. Tumors were histologically verified before the treatment in all cases. We discussed the indication for neoadjuvant chemoradiotherapy case to case in everyone patient at the multidisciplinary hospital committee, consisting of surgeons, gastroenterologists, imaging specialists, radiotherapists and clinical oncologists.

The neoadjuvant chemoradiotherapy was indicated to patients in good general status (ECOG -Eastern Cooperative Oncology Group -performance status ≤ 2) with histologically verified adenocarcinoma. According to the initial transrectal ultrasound examination and pelvic CT scan respectively, tumors were classified as T3 or T4 or N+ (TNM classification) [START_REF]International Union Against Cancer (UICC), TNM klasifikace zhoubnych novotvaru, Seste vydani[END_REF].

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Patients who had lower or middle rectal tumors within 12cm from anocutaneous verge, were prospectively enrolled into our study. Radiotherapy (RT) was performed by a linear accelerator to the pelvic region in the dose of 45.0-50,4 Gy in 25-28 fractions given within 5-5.5 weeks. 3-or 4-field method with multileaf collimator was used (three-dimensional -3D conform RT). Simultaneously with the radiotherapy, capecitabine in the dose of 825 mg/m 2 twice daily was given all time long (5 weeks). All patients completed the scheduled treatment. Toxicity of the neoadjuvant chemoradiotherapy was assessed according to the EORTC/RTOG criteria. Within 4 to 8 weeks from the completion of the neoadjuvant chemoradiotherapy the patients underwent the surgery. The surgery was carried out in a single hospital by a single team.

Follow-up CT and TRUS were performed close before the surgery. The procedure was initiated in laparoscopic way in all cases. Both total mesorectal excision (TME) and abdominoperineal amputation (APR) were carried out by "nerves sparing surgery" method.

We performed colonic lienal flexure deliberation in most patients with low anterior resection (LAR). All events leading to surgical tactic modification and iatrogenic lesion treatment outside the planned resection extent were assessed as intraoperative complications. All surgical and non-surgical complications reported until day 30 after surgery we considered as early postoperative complications.

Statistics

We used the Fischer exact test to test the difference between groups according to gender. The Mann-Whitney U test was used to compare the age, surgery duration, postoperative hospital stay, distance between the tumor and anocutaneous verge and number of lymph nodes assessed. The analysis was performed by software SPSS (SPSS Inc, Chicago IL) and SAS

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(SAS Institute, Cary NC). Significance level below 0.05 was considered statistically significant.

Results

Patients

From January 2005 to December 2007 we treated 78 patients, 62 men and 16 women.

Average follow-up was 23.9 months, median 24 (7-39). Average age was 62 years, median 62.8 years (27 -84). Most of patients had tumor assessed as T3 (72 %). All tumors were located within 12cm from the anocutaneous verge; median distance was 6cm. Stratification of patients according to the TMN classification is in Table 1.

Toxicity of the neoadjuvant therapy

The toxicity of the neoadjuvant chemoradiotherapy was assessed according to the EORTC/RTOG criteria. No patient had grade 4 toxicity, grade 3 toxicity occurred in 2 patients only -both were hematological (neutropenia). Grade 2 toxicity had 23 patients -10 had gastrointestinal, 9 had dermatologic and 2 genitourinary symptoms. Hand foot syndrome did not occur in any patient.

Type of surgical procedure

Sphincter-preserving surgery was possible to carry out in 47 % of cases only, but patients with abdominoperineal amputation (APR) had significantly more caudally located tumor (5cm vs. 7cm, p=0,01). Patients with abdominoperineal amputation were significantly older too (p=0,01). Groups were comparable according to hospital stay, time of surgery and number of assessed lymph nodes (Table 2). Non surgical complications we had in 3 cases -1 pneumonia, 1 urinary retention and 1 paresis of brachial nerve.

Response to the treatment

Downstaging was achieved in 54 patients (Table 1). 58% patients with advanced rectal carcinoma had pathologically negative lymph nodes after neoadjuvant CHT/RT. From all patents in the group almost 25% were initially as T4 stage according to the transrectal sonography (TRUS) and CT, only in 2 patients the subsequent pathological classification was ypT4. Pathological complete response was reported in 8 patients. All patients underwent radical surgery.

Discussion

Neoadjuvant concomitant chemoradiotherapy

Neoadjuvant concomitant chemoradiotherapy is standard part of the treatment of patients with the locally advanced rectal cancer in effort to downstaging achievement, improved tumor operability, improved local disease control and the most important -overall survival.

Downstaging was achieved in our work in 69% patients. Pathological complete response we

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achieved in 10%. These data are comparable to other cohorts in the literature. Outcomes of the phase II trials of concomitant chemoradiotherapy with capecitabine are in Table 3 [START_REF] Dupuis | Capecitabine (X) chemoradiation (CRT) in the preoperative treatment of patients (pts) with rectal adenocarcinomas: a phase II GERCOR trial. Abstract 3538[END_REF][START_REF] Wong | A phase II trial of preoperative capecitabine and concurrent radiation for locally advanced rectal cancer Abstract 281[END_REF][START_REF] Krishnan | Phase II study of capecitabine (Xeloda) and concomitant boost radiotherapy in patients with locally advanced rectal cancer[END_REF][START_REF] Velenik | Capecitabine as a radiosensitizing agent in neoadjuvant treatment of locally advanced resectable rectal cancer: prospective phase II trial[END_REF][START_REF] Korkolis | Pre-operative chemoradiotherapy with oral capecitabine in locally advanced, resectable rectal cancer[END_REF](18)[START_REF] Craven | Preoperative radiotherapy combined with 5 days per week capecitabine chemotherapy in locally advanced rectal cancer[END_REF][START_REF] Kocakova | Preoperative radiotherapy and concomitant capecitabine treatment induce thymidylate synthase and thymidine phosphorylase mRNAs in rectal carcinoma[END_REF][START_REF] De Bruin | Preoperative chemoradiation with capecitabine in locally advanced rectal cancer[END_REF].

Slovenian study reported pathological complete response in 9 % in cohort of 57 patients; downstaging they achieved in 49% [START_REF] Velenik | Capecitabine as a radiosensitizing agent in neoadjuvant treatment of locally advanced resectable rectal cancer: prospective phase II trial[END_REF]. Toxicity and efficacy was assessed in the Greek study in group of 30 patients [START_REF] Korkolis | Pre-operative chemoradiotherapy with oral capecitabine in locally advanced, resectable rectal cancer[END_REF]. In their work downstaging was in 75% patients, pathological complete response was high -in 23% of them. In comparison to our cohort, 17% patients with T4 tumor were enrolled into this trial, while almost 25% patients in T4 stage were enrolled into our cohort, but only in 2 cases the disease was subsequently classified as ypT4. Grade 3 toxicity was seen in 10% of patients (leucopenia), in our cohort it is 3% only.

Intraoperative and early postoperative complications were similar -20%.

Side effects

Capecitabine is radiosensitizer with different toxicity profile than continual or bolus administration of 5-fluorouracil. Administration of capecitabine can lead into side effectshematologic (leucopenia, thrombocytopenia, anemia) or non-hematologic (fatigue, stomatitis, nausea, vomiting, diarrhea, dermatitis, hand-foot syndrome). The most common complication of simultaneous administration of capecitabine and radiotherapy is acute gastrointestinal toxicity. It is 12 -34% in grade 2 and 3 toxicity (18). It is similar to our results.

Low presence of hand-foot syndrom is, in our opinion, caused by relatively short time of administration of capecitabine. Most studies, where this syndrome is recorded, are carried out in patients with metastatic disease when the time of administration is longer. Hematological toxicity of grade 3 and 4 is low too, in comparison to bolus or continual administration of fluorouracil [START_REF] Hoff | Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with M A N U S C R I P T A C C E P T E D ARTICLE IN PRESS metastatic colorectal cancer: results of a randomized phase III study[END_REF].

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Low presence of grade 3 adverse effects, similar to our results, was reported in a paper of Dutch authors, the same percentage -3% only in 60 cured patients [START_REF] De Bruin | Preoperative chemoradiation with capecitabine in locally advanced rectal cancer[END_REF]. Pathological complete response was reported in 13%. Another Slovenian study reported pathological complete response in 9% in 57 patients; downstaging they achieved in 49% [START_REF] Velenik | Capecitabine as a radiosensitizing agent in neoadjuvant treatment of locally advanced resectable rectal cancer: prospective phase II trial[END_REF].

Neodjuvant concomitant chemoradiotherapy was well tolerated in our patients and there was no reason to interrupt the treatment. Pathological response is a proven factor influencing overall survival; therefore there are efforts to achieve the highest response rate possible without an unacceptable toxicity [START_REF] Rosenberg | Histopathological response after preoperative radiochemotherapy in rectal carcinoma is associated with improved overall survival[END_REF].

Pathological N stage

The pathological N stage is very important prognostic factor for overall survival too. In our paper almost 60% of patients had negative lymph nodes, in the Craven's study the figure was similar [START_REF] Craven | Preoperative radiotherapy combined with 5 days per week capecitabine chemotherapy in locally advanced rectal cancer[END_REF]. Lymph nodes were originally assessed positive in 49 patients (63 %). But we have to realize, that an exact method for determining preoperative positivity of lymph nodes does not exist.

Radical lymphonodectomy belongs to criteria of oncological radicality too. Quantity of lymph nodes removed is determined by several factors. The first factor is the patient alone, according to his anatomic circumstances what determines the quantity of lymph nodes in the resected region. The second factor is the surgeon alone, who can by the surgical method, technique, experience and the extent of resection significantly influence the quantity of lymph nodes.

The third factor is the pathologist by his way of specimen processing and by the precision of the assessment determines pN component of the TMN classification of the colorectal cancer.

The number of examined lymph nodes is usually lower following the neoadjuvant therapy [START_REF] Wichmann | Effect of preoperative radiochemotherapy on lymph node retrieval after resection of rectal cancer[END_REF], in our cohort it was 14-18 lymph nodes in average. This finding we can confirm in our

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cohort of patients operated without the neoadjuvant therapy by the same team of surgeons, where the average number of examined lymph nodes was 24.9 [START_REF] Skrovina | Laparocopic Resection of rectal cancer: evaluation of perioperative results of the primary resection and resection after preoperative chemoradiotherapy[END_REF].

Anastomotic leak

One of the most severe surgical complications is the anastomotic leak following the lower rectal resection with total mesorectal excision, which is reported from 1% to 24%. The anastomotic leak was seen in 11% of cases in our cohort of patients operated by the sphincterpreserving approach following the pre-surgical chemoradiotherapy. It was necessary to treat the symptomatic dehiscence of the anastomosis by re-operation in 5% only. Sauer et al. from the German Rectal Cancer Study Group report in their multicentre randomized study postoperative complication in patients following the preoperative chemoradiotherapy compared to 34% of postoperative complications in a cohort of patients operated primarily with the intention of postoperative chemoradiotherapy (p = 0.68). They report the leak of anastomosis in 12% of patients following the preoperative chemoradiotherapy compared to 11% patients treated by primary surgery (p = 0.77). In the group of preoperative chemoradiotherapy the mortality was 0.7% vs. 1,3 % in the other group (p = 0,41) [START_REF] Sauer | German Rectal Cancer Study Group, Preoperative versus postoperative chemoradiotherapy for rectal cancer[END_REF]. The mortality was 0% in our cohort.

In the randomized multicentre trial published by Swedish authors RECTODES (REctal Cancer Trial On DEfunctioning Stoma) the outcomes of patients with rectal cancer within ≤ 15cm from the anal verge with or without primarily established protective ileostomy were reviewed. The presence of the symptomatic leak was reported in 19 % of cases, in patients with protective ileostomy in 10%, without the primarily established ileostomy in 28%. Urgent re-operation was necessary in 9% of patients with stoma and in 25% of patients operated without protective ileostomy [START_REF] Matthiessen | Defunctioning stoma reduces symptomatic anastomotic leakage after low anterior resection of the rectum for cancer, a randomized multicenter trial[END_REF].

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The trials with preoperative concomitant chemoradiotherapy with 5-fluorouracil (5-FU) led into local disease control improvement, to the tumor downstaging, but with no difference in disease dissemination and overall survival. This is the argument for searching of new cytostatic agents or their new combinations. Capecitabine is one of them. The low toxicity and achieved pathological responses raises the question, whether the combination with other cytostatic agents could improve the rate of pathological complete response and thus also overall survival in the group of patients with locally advanced disease. Several phase I and II trials have been published, especially the combinations of capecitabine with irinotecane and oxaliplatin. The pathological complete response is usually more than 20% (27-30), but the toxicity of the treatment is higher.

Conclusion

The aim of the preoperative chemoradiotherapy is, but overall survival, to achieve downstaging of the tumor and to improve operability with eventually increased rate of the sphincter-preserving operations. However, this therapy should not be burdened by increased number of severe complications. We have demonstrated very good tolerability and efficacy of the concomitant chemoradiotherapy with capecitabine in our work, which can replace the continual administration of 5-fluorouracil in this indication. We have also demonstrated suitability and low rate of complication of the subsequent laparoscopic operation. The pathological complete response is by this approach according to the literature 9-20%, results probably could be improved by adding another cytostatic agent.

We did not register any direct relation between toxicity of capecitabine and laparoscopic surgery.

Proclamation:

  Convenient safety profile of capecitabine has been recently demonstrated in randomized phase III trials in comparison with bolus FUFA; the preference of oral form of chemotherapy by patients too (9) Diarrhea, local skin reactions and hand-foot syndrome are the most common side effects of concomitant chemoradiotherapy with capecitabine. Continual administration of 5-fluoruracil or oral administration of capecitabine during all the time of radiotherapy are standard concomitant neoadjuvant CHT/RT treatment in local advanced rectal cancer now.

  We had to carry out conversion of laparoscopy into open surgery in 13 cases. It was caused by tumor size in 9 of them.Surgical complicationsM A N U S C R I P T A C C E P T E D ARTICLE IN PRESSIntraoperative complications we had in 4 patients. The urethral lesion required conversion of laparoscopic resection to an open surgery. All other intraoperative complications (small rectal lesion, small urinary bladder lesion and stapler failure) were solved by laparoscopic approach and no further complications were recorded in time of the postoperative period.Average hospital stay was 10 days. No patients died due to treatment complications. Surgical postoperative complications (until day 30) occurred in 7 cases. Anastomotic leak we had in 4 cases from 37 patients after low anterior resection of rectum, but in 2 patients re-operation was needed only. 4 patients had to undergo re-operation during the early postoperative period.

  ACV = Distance between the lowest tumor edge and anocutaneous verge M A N U S C R I P T A C C E P T E D ARTICLE IN PRESS

Table 2

 2 Comparison of the patient cohort according to the surgical procedure

	LAR	APR	P value

Table 3

 3 Results of trials with concomitant chemoradiotherapy with capecitabine

	Chemotherapy	Radiotherapy (Gy)	Patients	Pathological	Reference
			(Number)	CR
			TN stages
	Capecitabine 875	45 Gy, (1.8 Gy/fr.)	51 pts	24 % + 12 %	13
	mg/m 2		T3, T4, or	nCR
	BID		N+
	Capecitabine 875	50.4 Gy (1.8 Gy/fr.)	18	12 % +12 %	14
	mg/m 2		T3, T4, or	nCR
	BID		N+
	Capecitabine 825	52.5 (30 fr.)	51	18 %	15
	mg/m 2		T3 or T3N1
	BID
	Capecitabine 825	45 Gy in 25 fr. In 5	57 pts	9 %	16
	mg/m 2	weeks	Resectable
	BID		stage II/III
	Capecitabine 825	50,4 Gy in 28 fr. in 5,5	30 pts	23 %	17
	mg/m 2	weeks	T3, T4, or
	BID		N+
	Capecitabine 1650	46 Gy in 23 fr. (pelvis) +
	mg/m 2 daily	4 Gy (2 fr.

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All authors proclaim no financial and personal relationships with other people or organizations that could inappropriately influence their work.


Neil Bhardwaj
email: neilbhardwaj@yahoo.co.uk

A D Strickland

F Ahmad

M El-Abassy

B Morgan

G S M Robertson

D M Lloyd

Strickland Ad

Robertson Gsm

Lloyd Dm

Microwave Ablation for Unresectable Hepatic Tumours: Clinical Results using a Novel Microwave Probe and Generator

published or not. The documents may come

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Abstract

Background: Microwave ablation is an in situ method of tumour destruction used to treat patients with unresectable liver tumours. A new microwave generator and probe, designed to deliver high energy into solid tumours quickly has been developed at our institution. We report the results of its use in patients with unresectable liver tumours treated by a single surgeon in a single institution.

Methods: Thirty-one patients with 89 unresectable liver tumours were recruited into the study and underwent microwave ablation in a single procedure Results: There were no post-operative complications. At a median of 24 months post ablation, 15 patients were alive with 7 patients disease free. At a median of 26 months, 8 patients were alive with tumour recurrence but only 1 with local recurrence. The remaining 7 patients with recurrence were found to have new disease at locations remote from the ablation site. Discussion: Microwave tissue ablation using this novel generator and probe has a low local recurrence and complication rate. Overall survival is comparable to alternative ablation modalities and its ability to treat, even large tumours, with a single insertion of the probe makes it an extremely attractive treatment option.

INTRODUCTION

For patients presenting with primary and secondary liver tumours hepatic resection is currently the only potentially curative treatment. Such surgery is associated with a 5 year survival of 25-30% and a median survival of 25 months [START_REF] Fong | Clinical score for predicting recurrence after hepatic recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases[END_REF]. Regrettably, 75-80% of patients with these tumours are not amenable to surgical resection due to a variety of factors such as extrahepatic disease, tumour number or location or poor physiological reserve.

Patients with primary hepatocellular carcinoma (HCC) are frequently considered unresectable as the hepatic functional reserve is often poor due to underlying liver cirrhosis/hepatitis, thus making resection of large volumes of liver parenchyma unfeasible. This large cohort of unresectable and currently incurable patients has stimulated the expansion of ablation techniques whereby the tumours are destroyed in situ either by heating (radiofrequency or microwave) or by cooling (cryotherapy). At this institution a novel microwave applicator used to destroy liver tumours in patients deemed inoperable has been developed.

Technical data

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Microwave energy was generated using a magnetron at a frequency of 2.45GHz and delivered using a 6.4mm interstitial probe (Microsulis Medical Ltd, Denmead, UK). Microwave Tissue Ablation (MTA) uses electromagnetic energy at a high frequency, thus causing heating by constantly re-aligning polar molecules to the continuously fluctuating wave [START_REF] Swift | The histological features of microwave coagulation therapy: an assessment of a new applicator design[END_REF]. The purpose of this study was to report on the initial clinical experience of microwave ablation with particular reference to local recurrence and survival rates.

METHODS

Patient selection

A total of 31 consecutive patients were recruited into this study over a 4 year period (Table 1). After local ethical approval, all patients with primary or secondary liver tumours, deemed unsuitable for hepatic resection were recruited and treated with a curative intent. All patients with metastases had previously undergone excision of the primary tumour prior to the resection/ablation. All patients with colorectal liver metastases (n=24) had neo-adjuvant chemotherapy, usually in the form of oxaliplatin ± 5FU.

Patient suitability for microwave ablation and/or hepatic resection was

Ablation technique

All patients underwent MTA treatment at laparotomy except the patient with a hepatic parathyroid metastasis who was treated laparoscopically. The microwave equipment was set to deliver energy at a variety of powers ranging from 45-150 watts at the discretion of the surgical team. All ablations were carried out under real time Intra-operative Ultrasound (IOUS) monitoring with the aid of a Consultant Radiologist The formation of micro-bubbles from evaporated tissue water was visualised as a hyper-echogenic image (this became termed the 'thermal cloud'); treatment was considered complete when this thermal cloud overlapped the entire tumour by a 1cm margin. Following completion of the treatment the ultrasound image changed to a hypo-echoic one of similar dimensions to the initial image (Figure 1).

Temperature monitoring probes (thermocouples) were used in some cases to ensure cytotoxic temperatures (~55°C) were achieved at the lesion margins.

All tumours were treated with a single insertion of the applicator with

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treatment times varying between 2-4 minutes. On withdrawal of the probe, the track was heated at low power in an attempt to reduce any chance of tumour seeding and to aid haemostasis. Sixteen patients underwent a concomitant liver resection and 15 MTA only. All patients in this study had at least one tumour ablated although the maximum was 10. Peri-and postoperatively, patients were treated in a similar manner to those undergoing standard hepatic surgery.

Follow up

After discharge, all patients underwent 3-monthly cross-sectional imaging in the first year after surgery and subsequently 6 monthly imaging. The cross sectional data was interpreted by two Consultant Gastrointestinal Radiologists. The success of MTA was assessed by a number of criteria; post-operative complications, early post operative deaths (30 day mortality), local disease control (with particular emphasis being placed on the outcome of treatment to the larger lesions), disease free and overall survival.

Unsuccessful local disease control was defined as tumour recurrence at the site of previous ablation and determined by appearances on cross sectional imaging. Remote recurrence was defined as either new intra-hepatic tumour but distant to the previous ablation site or extra-hepatic disease.

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RESULTS

Morbidity and mortality

A total of 89 lesions were treated with MTA in 31 patients. The mean tumour diameter ablated was 20mm and the largest tumour treated was 50mm in diameter. MTA was well tolerated with none of the patients experiencing any of the post-operative complications reported following other alternative ablative modalities (bile leaks, abscess formation, pleural effusions, sepsis or haemorrhage from the probe track). Two patients died within 30 days of the surgery following myocardial infarctions; one at day 5 and another at day 30.

Survival and recurrence rate

During the follow up period of four years, a total of 15 patients were alive and 7 patients were disease free at a median of 24 months post ablation (range 12-33 months) (Figure 2). Eight patients were alive with tumour recurrence at a median of 26 months post ablation (range 12-40 months). Of these 8 patients with tumour recurrence, only 1 (3%) had demonstrable local recurrence as determined by cross-sectional imaging. The remaining 7 with hepatic tumour recurrence were noted to have new disease at sites remote from the ablation site. Three of these patients were noted to have developed with MTA, only 2 had demonstrable evidence of local recurrence, a patient based recurrence rate of 6%. Including the two early post-operative deaths, the overall survival in all patients was a median of 29 months and the 3 year survival was 40% (Figure 3).

Large tumours

A sub-analysis of the 31 patients in this series revealed 22 tumours greater than 30mm in diameter ablated in 14 patients. The mean diameter of the lesions was 35 mm (range 30-50mm). Six patients from this sub-group were alive at a median follow up of 28 months (range 12-40 months), 3 were tumour free at median of 29 months (range 12-33 months) post ablation (Figure 4). Of the remaining 3 patients, 1 (already mentioned above) had tumour at the ablation site along with remote hepatic disease and 2 had recurrences remote to the ablated area. Eight patients died and excluding the

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2 early post-operative deaths (already mentioned earlier), the median survival in these patients was 24 months (range 12-29 months). The 3 year survival in this sub-group was comparable to the 3 year survival of all patients.

DISCUSSION

Unresectable liver tumours present a major problem for healthcare providers.

We present our experience of (MTA) using a new microwave generator and probe in an otherwise incurable cohort of patients from one surgeon working in a single institution.

Complications

MTA appeared to be a well tolerated treatment in this patient group. None of the patients in this series showed evidence of sepsis, bile duct damage, thrombocytopaenia, or significant systemic upset. This compares very favourably with studies of alternative ablative modalities which have reported complications in up to 33% of the patients treated [START_REF] Mulier | Complications of radiofrequency coagulation of liver tumours[END_REF][START_REF] Livraghi | Treatment of focal liver tumours with percutaneous radiofrequency ablation: Complications encountered in a multicenter Study[END_REF]. In spite of the fact that some individuals underwent large volume microwave ablations, none of the patients in this study exhibited symptoms similar to that which

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have been described following large volume cryoablation ("cryoshock") [START_REF] Seifert | Prognostic factors after cryotherapy for hepatic metastases from colorectal cancer[END_REF].

Two patients (6%) died in the immediate post-operative period from myocardial infarctions confirmed at post-mortem. The livers of these patients were analysed and no abnormalities other than that of the ablated regions were noted. Both of these patients had documented cardiovascular disease and highlight the importance of careful patient selection for these procedures. Both patients were recruited at the beginning of the study and may reflect a learning curve often evident with new techniques. No other early post operative deaths were encountered during the study or until the time of writing. The 30-day mortality rate observed in this study is again at least comparable to other similar studies using RF and Cryotherapy [START_REF] Mulier | Complications of radiofrequency coagulation of liver tumours[END_REF][START_REF] Seifert | Prognostic factors after cryotherapy for hepatic metastases from colorectal cancer[END_REF].

Potential causes of local recurrence

Successful local disease control was evaluated using 3 monthly cross sectional imaging post ablation interpreted by two Consultant Gastrointestinal Radiologists. Of the 89 ablations using MTA, local disease control was achieved in 87 of 89 lesions and unsuccessful in two tumours (2%).

The two local recurrences in our series followed treatment of tumours 18mm and 30mm in diameter. These lesions were situated in close proximity to

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major hilar vessels in both cases. A tumour diameter of 30mm or greater and close proximity to major vascular structures are both well documented risk factors for tumour recurrence [START_REF] Pearson | Intraoperative radiofrequency ablation or cryoablation for hepatic malignancies[END_REF][START_REF] Curley | Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies: results in 123 patients[END_REF][START_REF] Wong | Radiofrequency ablation for unresectable hepatic tumours[END_REF][START_REF] Solbiati | Percutaneous radiofrequency ablation of hepatic metastases from colorectal cancer: long term results in 117 patients[END_REF][START_REF] Adam | Place of cryosurgery in the treatment of malignant liver tumours[END_REF][START_REF] Onik | Ultrasound-guided hepatic cryosurgery in the treatment of metastatic colon carcinoma. Preliminary results[END_REF][START_REF] Gazelle | Tumour ablation with radiofrequency energy[END_REF][START_REF] Bilchik | Radiofrequency ablation of unresectable hepatic malignancies: lessons learned[END_REF]. It is possible that the larger size of one of these tumours may be connected to its recurrence though many larger lesions were successfully treated in this series. It is however more likely that heat dissipation due to the blood flow in the nearby hilar vessels or poor probe placement are more likely explanations for these failures.

Encouragingly the 3 year survival of patients with large tumours was comparable to the overall patient survival in this series. The low recurrence rate observed in our series is extremely encouraging and at least comparable to local recurrence rates reported in studies of RF, which range between 2-39% (6-9). Failure of local disease control following cryotherapy is estimated to be between 9-44% [START_REF] Adam | Place of cryosurgery in the treatment of malignant liver tumours[END_REF][START_REF] Onik | Ultrasound-guided hepatic cryosurgery in the treatment of metastatic colon carcinoma. Preliminary results[END_REF].

Survival

The prognosis of untreated liver cancers is poor and the patients recruited in this study were considered incurable by the current gold standard treatments.

A median survival of 29 months is far superior to the best 2 nd line palliative chemotherapy regimens, which report a median survival of 20 months [START_REF] Kelly | Systemic therapy for metastatic colorectal cancer:current options, current evidence[END_REF][START_REF] Goldberg | Advances in the treatment of metastatic colorectal cancer[END_REF]. The overall three year survival rate of 40% is comparable to results

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from similar studies of alternative ablation modalities. There is a paucity of data with respect to long term survival in RF trials. A recent review of RF ablation for unresectable liver tumours identified 6 studies which reported 3 year survival, ranging from 37%-58% [START_REF] Mckay | Current role of radiofrequency ablation for the treatment of colorectal liver metastases[END_REF]. The results from this study suggest that MTA is a viable treatment for this group of patients. It is however always difficult to compare data from different trials as for instance what is considered unresectable disease is subjective and is likely to vary between centres.

Mechanism of action of MTA

This trial observed tumour recurrence and patient survival rates which were comparable to those reported from similar trials using RF and Cryotherapy. However, complications rates, single insertion treatments for even large tumours and rapid treatment times are however far superior to other ablative modalities. MTA has several advantages over alternative treatment modalities which may account for these results. The mechanism by which it causes tumour destruction is integral to this. Thermal damage occurs within a microwave field radiating from the inserted probe, thereby heating an entire volume of tissue simultaneously and thus not relying on thermal conduction. This markedly reduces treatment times and the need for repeat

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insertions of the probe. RF and cryotherapy however, rely almost exclusively on thermal conduction to exert their cytotoxic effects. This is inefficient and time consuming in tissues with high water contents such as hepatic colorectal metastases. This may in part, along with the requirement for multiple probe insertions to treat a single tumour, explain the relatively high rates of recurrence seen with RF and cryotherapy. Research work with MTA undertaken on porcine liver in this centre suggests that up to 80mm ablations are possible with a single insertion [START_REF] Strickland | Experimental study of large volume microwave ablation in liver[END_REF]. RF by contrast requires a total of six overlapping deployments of the electrode to completely ablate a 40 mm tumour [START_REF] Mckay | Current role of radiofrequency ablation for the treatment of colorectal liver metastases[END_REF]. This ability of MTA to treat tumours with a single insertion of the probe is invaluable as accurate re-insertions are often difficult intra-operatively due to the long standing acoustic shadows which form on the IOUS post ablation. In addition, continued reinsertion of the ablation probe has potential to damage greater volumes of hepatic tissue, a feature which may be of some importance in the treatment of primary liver tumours where the background liver parenchyma is cirrhotic.

Conclusion

This study suggests MTA using a new generation of microwave generator and probe is associated with a low recurrence and complication rate. It also

Fourteen

  patients died of disease progression at a median survival of 15 months, with only 1 patient with local and remote tumour recurrence. Of the total numbers of tumours treated (n=89), a local tumour recurrence rate of M A N U S C R I P T A C C E P T E D ARTICLE IN PRESS 2% was observed. Overall median survival was 29 months with 3 year survival of 40%.

  determined at the hepatobiliary cancer multi-disciplinary team meeting following clinical assessment and results of cross-sectional imaging (MRI/CT).

  extra-hepatic disease. During the follow-up period, 14 patients died of disease progression, with a median survival in this group of 15 months post ablation (range 9-42 months). One of these patients died at 9 months post ablation and had local and remote tumour recurrence. Of the total numbers of tumours treated (n=89), a local tumour recurrence rate of 2% was observed in the four years of this study. Of the all the patients treated (n=31)

  has the ability to rapidly treat even large tumours with a single insertion of the probe. It may have a role in the treatment of patients with unresectable liver tumours either primarily or as an adjunct to standard hepatic resection.Although the numbers of patients treated in this study are small, the initial results are encouraging and at least comparable to those achieved with alternative ablative techniques. Future developments such as percutaneously delivered MTA antennas and laparoscopic treatments may further expand the indications for this treatment.

Figure 1 .Figure 2 .Figure 4 .

 124 FIGURES

Acknowledgments: Microsulis medical equipment, Professor Nigel Cronin, Peter Clegg (Bath University) and United Hospitals Leicester for the grant to Mr Andy Strickland.


M.D R R De Vries

research physician J A Nieuwenhuijzen

A Vincent

PhD, statistician H Van Tinteren

PhD, statistician S Horenblas
email: s.horenblas@nki.nl

R R De Vries¹

J A Nieuwenhuijzen¹

S Horenblas¹

resident in Vincent

Survival after cystectomy for invasive bladder cancer

Keywords: Bladder neoplasms, cystectomy, transitional cell carcinoma, survival, high risk non muscle invasive bladder cancer

Aim

To determine the difference in survival after cystectomy between patients presenting with primary muscle infiltrating bladder cancer and patients with progression to muscle infiltration after treatment for initial non muscle invasive bladder cancer (NMIBC).

Patients and Methods

We retrospectively analyzed the files of 188 patients who underwent cystectomy for transitional cell carcinoma between 1987 -2005. Two groups were defined: patients presenting with muscle invasive tumours and those progressing to muscle invasion after initial treatment. This second group was further divided into low-intermediate and high risk according to the EAU grouping for NMIBC.

Results

The 5-year disease specific survival (95% confidence intervals) for all patients was 50%(42%-59%); 49%(40%-60%) in the primary muscle infiltrating group and 52%(37%-74%) in the progressive group (p=ns). The 5-year disease specific survival in the progressive group according to EAU risk groups was 75%(58%-97%) for the initially diagnosed low-intermediate risk tumours and 35%(17%-71%) for the initially diagnosed high risk tumours (p= 0.015). The percentage of patients with non-locally confined tumours (pT3/4-N0 // any pT-N+) was 31% // 45% and 24% // 46% in the primary muscle infiltrating and progressive group, respectively.

Introduction

Non muscle invasive bladder cancer (NMIBC) comprises of a heterogenic group of tumours, with variable biological behavior and malignant potential. The probability to progression to muscle invasion varies from 6%-48% . [START_REF] Sylvester | Predicting Recurrence and Progression in Individual Patients With Stage Ta T1 Bladder Cancer Using EORTC Risk Tables: a Combined Analysis of 2596 Patients From Seven EORTC Trials[END_REF] Identifying the patients in whom NMIBC will progress despite bladder sparing therapy is a major challenge. The 2006 EAU guidelines on bladder cancer defined three risk groups for NMIBC: a low-risk group (single, low grade (G1), non-invasive (Ta) lesion smaller than 3 cm); a high risk group (lamina propria invasion (T1), high grade (G3), multifocal or highly recurrent, or CIS) and an intermediate group with all other non muscle invasive tumours (e.g. Ta-T1, G1-G2, over 3 cm ). [START_REF] Oosterlinck | Guidelines on TaT1(non-muscle invasive) Bladder cancer[END_REF] In low risk NMIBC, a bladder sparing regimen is uniformly advised, consisting of transurethral resection (TUR) followed by a single immediate instillation of intra-vesical chemotherapy. High risk disease is usually treated with TUR followed by intra-vesical BCG. The undisputable indication for cystectomy is histological evidence of muscle invasion during follow-up. We hypothesized, that the intensive monitoring of patients with NMIBC during bladder sparing management would

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4 lead to an early discovery of muscle invasion with consequently better survival than patients presenting initially with muscle invasion. To test this hypothesis, we compared survival in patients presenting with NMIBC that progressed to muscle invasive disease with patients presenting with primary muscle invasive bladder cancer, all treated by cystectomy and regional lymph node dissection. When imaging was highly suspicious for tumour positive lymph nodes, a bilateral regional lymph node dissection or fine needle biopsy was performed before cystectomy.

Otherwise patients underwent regional lymph node dissection at cystectomy. The accuracy of clinical staging was assessed by comparing clinical primary stage and pathological tumour stage after cystectomy.

Treatment

Patients with NMIBC were initially treated with TUR at the referring hospitals. Patients with muscle-invasion at follow-up were referred for cystectomy and regional lymph node dissection. Boundaries of pelvic node dissection until 2000 where: distally the circumflex vein and the node of Cloquet, laterally the external iliac artery, medially the bladder and the prostate and proximally the hypogastric artery. From 2000 the boundaries were enlarged proximally to the crossing of the ureter over the common iliac artery and laterally to the genitofemoral nerve. Patients with histologically or cytologically proven positive lymph nodes before cystectomy received neo-adjuvant chemotherapy. Since 2000 patients considered high risk for recurrence after cystectomy (≥ pT3and/or ≥N1) have been randomized between early or late chemotherapy, according to the EORTC-

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Statistical analysis

Disease specific survival was defined as time between cystectomy and death of disease or treatment or last contact. Survival estimates and 95% confidence intervals were calculated using the Kaplan-Meier method. Log-rank tests were used to assess differences in survival between the primary muscle infiltrating and progressive group. To evaluate the impact of EAU risk stratification on survival we compared the initially lowintermediate non muscle invasive with the initially high risk non muscle invasive tumours in the progressive group.

A multivariate Cox proportional hazards model was constructed to determine the association of gender, focality (single or multiple), age, and patient grouping (primary and progressive muscle infiltrating) with disease specific survival. A backward stepwise elimination procedure was performed to identify factors associated with survival at the 0.05 significance level. The association between number of TUR (≤2 TUR and >2 TUR before cystectomy) disease specific survival, tumour upstaging after cystectomy was assessed in the progressive invasive patient group using a log-rank test and Chi square test.

Differences in characteristics of patients in progressive and primary muscle infiltrating groups were tested using chi-square, Fisher-exact and Mann-Whitney-Wilcoxon tests where appropriate. No imputation of missing data was performed. The significance level was set at 0.05 for all tests.

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8

Results

Patient Characteristics

134 patients presented with primary muscle infiltrating bladder cancer and 54 patients with progressive bladder cancer. The distribution of patient and tumour characteristics between these two groups are presented in Table 1a. Mean age at cystectomy was 61 years and the male to female ratio was roughly 3:1. The definitive pathological stage of the primary tumour (pT-stage) was higher than the pathological stage of the TUR specimen in 19% of primary muscle infiltrating patients, while 2% had pathological stage lower than clinical stage. This was 26% and 0% for the progressive group. Pathological lymph node stage (pN) was higher than clinical lymph node stage (cN) in 16% of primary patients and 26% in the progressive group. There was no significant difference in stage distribution after cystectomy between both groups. The proportion of patients with multifocal tumours was significantly higher in the progressive group than in the primary muscle infiltrating group (p<0.001) (see Table 1a).

Patients' characteristics and both clinical (NMIBC and muscle invasive stage) and pathological stage for the progressive subgroups are shown in table 1b. There was no significant difference in stage distribution after cystectomy between both subgroups.

Both the definitive pathological stage of the primary tumour (pT-stage) and the pathological lymph node stage (pN) were higher than in the TUR specimen in 28% (N=7) of the low risk patients, and 24% (N=7) in the high risk patients. No patients had lower pathological T or N stage than clinical stage.

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Treatment History A total of 61 patients received neoadjuvant chemotherapy, 46 in the primary muscle infiltrating group and 15 in the progressive invasive group. In the primary muscle invasive group 44 achieved a complete or partial response to neoadjuvant chemotherapy, in the progressive invasive group this was 15. Ten patients received adjuvant chemotherapy, 7 in the primary muscle infiltrating group and 3 in the progressive invasive group. There was no significant difference in the number of patients receiving either neoadjuvant or adjuvant chemotherapy.

In the high-and low-risk progressive subgroups, neoadjuvant chemotherapy was given to 4 and 11 patients respectively, and adjuvant chemotherapy was given to two and one patients respectively. Again there was no significant difference in clinical response to neoadjuvant treatment.

Survival

At the time of analysis 89 patients had died, all but twelve of either bladder cancer or treatment. The median follow-up after cystectomy was 3.4 years, which was not different between groups.

The 5-year disease specific survival estimate (95% confidence intervals) for all patients was 50% (42%-59%); 49% (40%-60%) in the primary muscle infiltrating group and 52% Patients with organ confined lymph node negative tumours (pT2N0) had a 5-year disease specific survival of 80% (65%-97%) and 93% (82%-100%) for the primary muscle infiltrating group and the progressive group respectively (p=ns, Table 2a). Stratified by risk group these figures were: 100% and 88% (67%-100%), for the low and high risk groups respectively. (Table 2a, p=ns).

Survival at 5 years of patients with non-organ confined disease and tumour negative nodes was: 56% (42%-75%) for the primary muscle infiltrating group and 37% (14%-97%) for the progressive group (p=ns, table 2a). Stratified by risk group: 71% (45%-100%) and 0%, for the low and high risk groups respectively (Table 2a; p=ns).

Eighty-five patients had tumour positive lymph nodes after cystectomy: 60 (45%) in the primary muscle-invasive group and 25 (46%) in the progressive group. Stratified by risk group: there were 10 (40%) in the low risk and 15 (51%) in the high risk subgroup.

The 5 year disease specific survival rates for lymph node positive patients were 28% (17%-46%) for the primary muscle infiltrating group and 40% (24%-69%) for the progressive group. Stratified by risk group: 63% (37%-100%) and 25% (9%-67%), for the low and high risk groups respectively. (Table 2a; p=0.04)

In the multivariate analysis gender was significantly associated with disease specific survival. Females had a higher risk of dying from disease than males (HR=2.16 (1.7-2.8); p=0.0009). Focality, age, and patient grouping (primary vs. progressive) showed no significant association with survival. (Table 2b)

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Finally, there was no significant association between the number of TUR disease specific survival, and upstaging in the progressive group.

Discussion

The undisputable indication for cystectomy in patients with NMIBC is progression to muscle invasion. Follow up schedules are aimed at the earliest possible detection of progression, leading to the best possible survival. In our study all patients were followed up according to the EAU-guidelines which in theory should lead to low stage disease at cystectomy.( 2) Nevertheless, patients with NMIBC progressing to muscle invasion had no better survival after cystectomy than patients with primary muscle invasive bladder cancer. This is in accordance to others, while some showed an even worse survival. [START_REF] Schrier | Prognosis of Muscle-Invasive Bladder Cancer: Difference Between Primary and Progressive Tumours and Implications for Therapy[END_REF][START_REF] Yiou | Outcome of Radical Cystectomy for Bladder Cancer According to the Disease Type at Presentation[END_REF][START_REF] Lee | Early-Stage Bladder Cancer Surveillance Does Not Improve Survival If High-Risk Patients Are Permitted to Progress to Muscle Invasion[END_REF] These studies suggest that cystectomy should ideally be done before any bladder muscle invasion occurs or at a stage when the bladder tumour is still locally confined. This notion is not new and has been echoed by those who advocate an early cystectomy.

Understaging, swift progression and poor survival of the progressive group

What could be the reasons and explanations for these findings? First, standard follow up was unable to detect occult progression, exemplified by 26% under staging in non locally confined disease and 26% under staging in tumour positive lymph nodes. It is a sobering fact that despite close monitoring these figures are not different at all from clinical under staging in patients presenting primarily with invasive disease.(8) Because our hospital is a tertiary center patients with higher stages are

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12 referred to our hospital, exemplified by a relatively high incidence (45%) of positive lymph nodes after cystectomy in both groups as compared to contemporary cystectomy series. [START_REF] Ficarra | Correlation Between Clinical and Pathological Staging in a Series of Radical Cystectomies for Bladder Carcinoma[END_REF][START_REF] Ghoneim | Radical Cystectomy for Carcinoma of the Bladder: 2,720 Consecutive Cases 5 Years Later[END_REF][START_REF] Stein | MANUSCRIPT 17 Cystectomy in the Treatment of Invasive Bladder Cancer: Long-Term Results in 1,054 Patients[END_REF] Secondly the swift occurrence of progression, indicated by 24% non locally confined disease and 46% lymph node invasion after cystectomy in the progressive group. Most of these patients have a history of non muscle invasive disease and are under surveillance for NMIBC so one would expect these percentages to be lower than in the primary invasive group.

Thirdly the poor survival rates of high-risk non invasive bladder cancer progressing to muscle invasion. This was significantly worse compared to patients with a lowintermediate-risk tumour (76% versus 20%). As there was no difference in TNM distribution after cystectomy for both groups this difference in prognosis must be explained by other factors, like tendency for early dissemination of these high grade tumours. This underlines the poor prognosis of the high-risk group providing further weight to arguments for early cystectomy. Five year survival rates of approximately 90% have been published when cystectomy is performed before evidence of muscle invasion. (10;11) Our study also demonstrates a rather good prognosis for patients with muscle invasive disease after cystectomy for locally confined disease.

Fourthly the urological community is alert on the high risk of progression in patients presenting with T1G3 tumours and the subsequent poor survival.(1) However our study suggests equal (poor) survival rate in high grade Ta-disease. [START_REF] Millan-Rodriguez | Primary Superficial Bladder Cancer Risk Groups According to Progression, Mortality and Recurrence[END_REF] In addition we find patients with low grade (low or intermediate risk) tumours that have progressed rapidly to a locally advanced tumour with lymph node metastases.

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The number of prior TUR and survival Analysis of TUR prior to cystectomy did not show survival differences and upstaging in those who had less than 2 TUR in comparison to those with more than 2 TUR. This is in contrast to a recent study by Wiesner et al. who reviewed the files of 219 patients with non-muscle-invasive TCC that progressed to muscle invasion. They found tumour positive lymph nodes in 33 patients (15%). The number of TURs correlated with the prevalence of lymph node metastases. [START_REF] Wiesner | Lymph Node Metastases in Non-Muscle Invasive Bladder Cancer Are Correlated With the Number of Transurethral Resections and Tumour Upstaging at Radical Cystectomy[END_REF] Survival in women stage for stage is less than in males. Findings that are supported by others ( 14)

Optimal timing of cystectomy

How can we solve the dilemma of too early cystectomy (increase of survival but at the cost of too many bladders removed) and too late cystectomy (jeopardizing survival of the patient)?

In clinical practice, the heart of the matter lies in defining progression and the early notion of therapy resistance. In high risk disease the above notion has led to a "change of paradigm", advising early cystectomy before histological proof of muscle invasion. [START_REF] Herr | Can Restaging Transurethral Resection of T1 Bladder Cancer Select Patients for Immediate Cystectomy?[END_REF] Failures of BCG therapy in high risk disease are now defined as progression to higher grade or T-category, the appearance of carcinoma in situ during therapy and a recurrence The EORTC risk tables, based on six tumour characteristics (number of tumours, tumour size, prior recurrence rate, T category, carcinoma in situ, and grade) are currently the most accurate tool to predict the risk of recurrence and progression in non muscle invasive bladder cancer patients. (1;16) The major limitations of our study are the retrospective character, the potential selection bias, and the limited number of patients. Our patients with progressive non muscle invasive bladder cancer come from a large undefined pool of patients. Therefore our results can only be used as an illustration of the fate of patients progressing to muscle invasion.

It is our belief that follow-up should be aimed at the detection of failures at the earliest possible moment, preferably before muscle invasion has occurred. In this respect, identifying patients in whom initial therapy is not successful is the major challenge.

Conclusions

Despite close observation of patients treated for NMIBC, survival in patients who progress to muscle invasion is not better than patients presenting with primary muscle

6 Staging

 6 Preoperative assessment and patient selectionBetween 1987 and 2005, 286 patients underwent cystectomy for transitional cell carcinoma (TCC) at our institute. Being a tertiary referral centre, patients were referred after diagnosis and/or treatment at other hospitals. Reasons for referral were: NMIBC progressing to muscle invasive disease or muscle invasive disease at first diagnosis. Data from referring hospitals were reviewed for date of initial diagnosis of bladder cancer and follow-up until referral. Forty-four patients presented with high risk non muscle invasive urothelial cancer treated with cystectomy before muscle invasion and were excluded from analysis. Four patients were excluded from analysis because of incomplete data. Another 50 patients were excluded from analysis as they underwent salvage cystectomy after brachytherapy or external beam radiotherapy (EBRT). They have been reported earlier.[START_REF] Nieuwenhuijzen | Survival After Bladder-Preservation With Brachytherapy Versus Radical Cystectomy; a Single Institution Experience[END_REF]The remaining 188 patients were divided into two groups based on initial presentation. We distinguished a primary muscle invasive group: patients with muscle invasion at first presentation (pT≥ 2) and a progressive group: patients with a history of non muscle invasive disease progressing to muscle invasion after TUR with or without adjuvant intravesical therapy. The progressive patients were stratified according to EAU risk-categories after last TUR for NMIBC. (2) Patients with muscle invasive disease within three months after first TUR for non muscle invasive bladder cancer were included in the primary muscle infiltrating group.Clinical stage was determined by physical examination, TUR, chest x-ray, and pelvic/abdominal computerized tomography scan (CT-scan). All stages were converted to the IUCC 2002 TNM classification.[START_REF] Ch | TNM Classification of Malignant Tumours[END_REF]

(

  37%-74%) in the progressive group (Fig 1a, log-rank, p=ns); stratified by risk group: 75% (58%-97%) in the low and 35% (17%-71%) in the high risk tumours (Fig 1b p= M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 10 0.015). The difference in disease specific survival between muscle invasive and lowintermediate risk tumours was not significant (Fig 1c).

at both 3

 3 and/or 6 months. In low-intermediate risk disease, the indication for cystectomy M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 14 has traditionally been histological proof of muscle invasion. In this risk category the challenge is to better define failure, preferably before muscle invasion.

  infiltrating cancer. Patients with high-risk NMIBC who progress to muscle invasive disease before cystectomy have a worse prognosis compared to patients with lowintermediate risk NMIBC who progress to muscle invasion. The number of patients with locally advanced and lymph node positive disease was unexpectedly high in the M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 15 progressive group, underlining the need for improved identification of the patient in need of early cystectomy. For now, we advocate active restaging (re-TUR) during conservative management of non muscle invasive bladder cancer. The indication for cystectomy should be at a stage preferably before histological proof of muscle invasion, EORTC tables can be helpful. T-stage and grade progression are probably just as important signs for early cystectomy as the traditional criterion of muscle invasion. M A N U S C R I P T A C C E P T E D