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Rebuttal from Author re: Armin Pycha. FISH: ATool We Really Need? Eur Urol 2007;52:630–2

Antonio Alcaraz *

Department of Urology, Hospital Clinic, University of Barcelona,

Spain

High-risk non–muscle-invasive urothelial carcino-mas of the bladder (UCB) are those pT1, G3, multi-focal or highly recurrent, or carcinoma in situ (CIS)tumours. High-grade superficial transitional cellcarcinoma (TCC) has a significant risk of occult orsubsequent progression to muscle-invasive or meta-static disease. Such high-risk lesions deserveaggressive therapy with repeat resection in mostcases, followed by intravesical therapy, usually inthe form of bacillus Calmette-Guerin (BCG).

The recently released tables from the EuropeanOrganization for Research and Treatment of Cancer(EORTC) are useful tools to assess the risk ofrecurrence and progression. Developed from well-controlled randomised trials with adequate treat-ments and follow-up, they provide insight into therisks for individualised patients. Striking figures,such 78% progression rate at 5 yr for pT1 G3 tumourswith associated CIS, challenge the idea of transu-rethral resection of the bladder (TURB) plus intra-vesical instillations as the standard of treatment infavour of early cystectomy, especially consideringthe poor prognosis of muscle-invasive tumourswhen progressing from superficial ones [1].

1. Intravesical treatment

No major advances have been made in the last 30 yrsince Morales, in 1976, first described the utility ofBCG intravesical treatment in preventing recurrenceof high-risk superficial bladder tumours (HRSBTs).Well-designed clinical trials have proven the super-iority of BCG treatment over mitomycin in prevent-ing and delaying recurrences in the whole group ofhigh-risk superficial tumours.

Several trials failed to prove a decrease in theprogression rate after BCG treatment. Only when thedata on patients in the EORTC meta-analysisconducted by Sylvester et al [2] were pooled was a26% reduction found in the progression to muscle-invasive disease; this benefit mostly applied to thepatients in the BCG maintenance regimen arm.

DOIs of original articles: 10.1016/j.eururo.2007.03.001,10.1016/j.eururo.2007.03.068* Tel. +34 93 227 55 45; Fax: +34 93 227 55 45.E-mail address: aalcaraz@clinic.ub.es.

Nevertheless only 16% of patients included in theSouthwest Oncology Group (SWOG) study were ableto receive all scheduled doses of BCG, suggestingsignificant treatment-related morbidity for BCGmaintenance [3].

As proven for the data in avoiding recurrence andfurther failure to treatment, mitomycin is not faraway from BCG treatment [4]. Because mitomycinis a better tolerated treatment several effortshave been made to optimise instillations, namely,increasing concentration by reducing urine produc-tion, alkalinising the urine, using electromotive drugadministration (EMDA), and creating bladder wallhyperthermia.

Mengual et al [4] raise two important points intheir publication in the present issue of EuropeanUrology in which HRSBTs are monitored by mean offluorescence in situ hybridisation (FISH; UroVy-sion). Based on the capability of FISH to detectchromosome numeric alterations, the multitargettest UroVysion combines the detection of thenumeric alterations of chromosomes 3, 7, and 17,an epigenetic phenomenon secondary to thegenetic instability characteristic of UCB, and thedeletion of the 9p21 locus, an early event of papillaryUCB. First, 85% of the patients have a positive FISHtest after TURB, which indicates the presence ofurothelial cells carrying chromosome alterationscharacteristic of UC. The conclusion comes imme-diately that an adjuvant treatment is necessary toeradicate the remaining bladder tumour cancercells. Intravesical treatment is mandatory in theseHRSBT patients, as already assessed by the Eur-opean guidelines and others. As shown earlier, it ispossible to delay and even reduce the number ofrecurrences by using intravesical BCG. However, itis reasonable to have doubts about the final goalof reducing deaths or at least reducing tumourprogression achieved by the current standardtreatments.

After 30 yr of treating our patients with BCG andmitomycin, we should have the more ambitious goalof eradicating remaining bladder tumour cells. Newintravesical drugs and alternative therapies suchphotodynamic therapy warrant further research.

2. Predicting BCG failure

Although BCG immunotherapy has been widelyaccepted as the optimal treatment for CIS and high-grade superficial TCC, it has an associated risk offailure ranging from 38% to 50% at long term follow-up. Criteria for failure of intravesical therapy are notwell defined, but a total treatment and follow-uptime of at least 6 mo is necessary to identify early

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BCG failure. Changing to an alternative regimenbefore 6 mo is considered probably premature,ignores the delayed therapeutic effect of repeattransurethral resection and BCG, and artificiallyinflates response rates of salvage regimens. Ingeneral, patients with CIS are considered refractoryto BCG or failures when biopsies and cytology do notbecome normal after the initial course of six weeklyinstillations.

The second important conclusion in the Mengualet al study is that patients with a positive FISH testafter BCG are at higher risk of recurrence. Twenty-nine of 65 (44.6%) patients had a positive FISH resultafter BCG. Twenty-four of these 65 (36.9%) patientspresented recurrence with a mean time follow-up of13.3 mo (range: 9.8–18.6 mo). This is in agreementwith larger series showing a recurrence rate of36.6% after 26 mo [5] and 53.3% after 3.6 yr inpatients with associated CIS [6]. Patients with apost-BCG positive FISH test were 2.7 times morelikely to have recurrence than those with negativetests (66% actuarial risk of recurrence at 2 yr).Six patients (25%) had recurrence as a muscle-invasive tumour and three others also requiredcystectomy for persistent CIS (40%). Moreover,six patients (25%) had recurrence to HRSBT withuncertain prognosis.

Because recurrence after BCG therapy seems agood surrogate for cancer-free survival, it is impor-tant to select those patients at high risk ofrecurrence to make clinical decisions both in thefollow-up schema and the treatment decisionprocess, which includes second-line intravesicalinstillation or cystectomy or both.

Several attempts to predict BCG failure targetinghost, tumour, and immunologic parameters canadd some information to the clinical risk factorsdefined in the EORTC risk tables [2], namely, tumournumber, size, and prior recurrence to predicttumour recurrence and tumour stage, grade, andCIS for progression.

Several studies have shown a prognostic value ofurine levels of interleukin-2, -8, and -18 to predictresponse to intravesical BCG [7]. p53 status immuneexpression in the tumour also proved to predict theoutcome of BCG therapy. Unfortunately, none ofthem is currently used in clinical practice.

Finally, FISH (UroVysion) has proved its abilityto predict recurrence after BCG in two studies [4].The rationale of both studies is the anticipatoryvalue of a positive FISH test to detect recurrences.Yoder et al [8] showed that two thirds of patientswith a positive FISH test and a negative cytoscopydeveloped a recurrence in a period of 30 mo, whichis in full agreement with the data shown by

Mengual et al [4] in the subgroup of patients treatedwith BCG, proving the statement by Pycha et al [9]that BCG does not change the chromosome pattern,contrary to the phenotypic changes in cytology,making FISH a more adequate tool after BCGtreatment.

Probably, even more important than FISH provingits utility in monitoring BCG failure is the fact that agenetic-based test can predict tumour recurrencebased on the presence of specific genetic alterationscharacteristics of UC that precede the developmentof the tumour.

3. Role of FISH in the follow-up

We agree most comments from Pycha [10] in theeditorial in the present issue of European Urologyreferred to the lack of standardisation and multi-centric studies in the development of FISH. However,specific indications to use FISH in the follow-up ofnon–muscle-invasive UCB seem reasonable.

The follow-up of HRSBTs is based in the combi-nation of cystoscopy and cytology. Cystoscopy is farfrom the perfect tool in the diagnosis of theseHRSBTs as proven by several reports using endo-scopic photodynamic diagnosis (PDD). Cytoscopywith <90% sensitivity to detect recurrences have agood complement in cytology because it is able todetect >90% of the tumours and its specificity isalmost 100%. However, these striking figures applyonly for experienced pathologists and the techniqueis hampered by its subjectivity.

FISH (UroVysion) shows very similar sensitivityand specificity to cytology in HRSBTs, but it is aquantitative technique with some degree of sub-jectivity and interobserver variation that requiresexperienced readers to interpret the results. Becauseit does not make any sense to add a third test in thefollow-up of HRSBTs, it is unlikely that FISH willsubstitute for cystoscopy or cytology.

A totally different scenario is low-risk superficialbladder cancer (LRSBC) for which cytology has asensitivity no higher than 30%, a figure thatdiscourages many centres from using it and leavingcystoscopy as the only technique in the follow-up ofthese tumours. FISH, with a sensitivity around 60%,could replace cytology. A similar rationale could beapplied for upper urinary tract urothelial carci-nomas, where cytology has demonstrated a sensi-tivity of 30% for high-grade tumours, clearly lowerthan the 65% sensitivity of FISH (UroVysion), whilemaintaining similar specificity [11].

Together with the prognostic value of FISH afterBCG in HRSBT [4], a final potential utility of FISH inthe follow-up of both high- and low-risk UCB is to

doi:10.1016/j.eururo.2007.04.056

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clarify suspicious or equivocal cytology. In thissituation, in around 60–70% of patients a positiveFISH test is found.

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