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Kamat, Ashish M.a; Gontero, Paolob

doi: 10.1097/MOU.0000000000000551
NON-MUSCLE INVASIVE BLADDER CANCER: Edited by Ashish M. Kamat and Paolo Gontero

aMD Anderson Cancer Center, Houston, Texas, USA

bMolinette Hospital, University of Turin School of Medicine, Torino, Italy

Correspondence to Paolo Gontero, MD, Associate Professor of Urology University of Turin School of Medicine, Chair Division of Urology, Department of Surgical Sciences, Molinette Hospital, Bramante 88/90, 10126 Turin, Italy. Tel: +390116706518; e-mail:

Nonmuscle-invasive bladder cancers (NMIBCs) represent a heterogeneous group of diseases with broad differences in prognosis. This accounts for a large variation in the degree of aggressiveness in treatment options. The original categorization into three risk groups (low, intermediate and high risk), initially proposed by the EORTC and subsequently adopted with unsubstantial changes by current guidelines (European Association of Urology and American Urological Association) still represents a valuable clinical tool for decision making. This is mainly due to a significant correlation with the risk of progression to muscle invasive disease that varies from less than 1% in the low-risk category up to 25–50% in the high-risk group. Nonetheless, there is accumulating evidence suggesting that this categorization remains inadequate to fulfil current clinical needs chiefly in the intermediate- and high-risk categories where significant heterogeneity in prognoses exist. To overcome this limitation, a subclassification of the NMIBC at intermediate risk of progression based on prognostic factors has been suggested but not yet validated [1]. In this issue Brummelhuis et al. (pp. 557–562) focused on the recurrent low-grade Ta, one of the most controversial and challenging subtype of NMIBC. While belonging to the intermediate risk group, low-grade Ta harbours a favourable prognosis that may overlap that of the low-risk category. The authors warn against a potential risk of overtreating this condition and provide some evidence showing how less invasive procedures such as office fulguration or laser ablation and even active surveillance may prove equally effective. Above all, reduced treatment burden combined with a less intense follow up scheme for a disease subcategory with a favourable outcome may translate in improving patient's quality of life as well as cost-effectiveness of the most expensive oncological disease.

Even more challenging is the variability in clinical behaviour within the high risk category of NMIBC, posing an unresolved dilemma between intravesical Bacillus Calmette & Guerin (BCG) and early cystectomy. Mannas et al. (pp. 563–569) provide a comprehensive review of the main clinical and pathological risk factors for the T1 high grade (T1HG). By assessing the available evidence, they propose the presence of a single very high-risk factor or the simultaneous occurrence of multiple high-risk factors as strong indications in favour of an aggressive approach upfront. However, there is only limited evidence on how prognostic variables can be integrated in predictive models that allow to reliably estimate the risk of progression in T1HG. In a large retrospective cohort of T1HG receiving BCG, a combination of one or more of three independent predictors of unfavourable outcome among age more than 70, carcinoma in situ and tumour size above 3 cm accounted for a risk of progression that varied between 17% and 52% [2]. A reliable prediction of the optimal treatment of T1HG awaits validation of these rudimentary prognostic tools through prospective series integrating clinical variables with molecular markers.

While the controversy about T1HG disease continues, if we are faced with a shortage of BCG (which has occurred twice in last 5 years) then patients have limited alternatives to radical therapy. To address this, several task forces were convened and Abufaraj et al. (pp. 570–576) summarize some of the previous recommendations here. Measures that can be utilized include using intravesical chemotherapy induction and maintenance for patients with intermediate risk NMIBC. In high-risk patients, one can consider reducing the dose of BCG (so as to split the vials among multiple patients) or in select cases, BCG instillations can be terminated when the patient has completed one-year of maintenance. Where available, enhanced chemotherapy (e.g., heated mitomycin C or Synergo with mitomycin C) can be used when radical cystectomy is not feasible. As always, we must remember that in times of BCG shortage, immediate radical cystectomy should always be considered in highest risk NMIBC and a complete discussion of the risk benefit ratio should be done with patients. Since to date, no intravesical therapy has been shown to be as effective as intravesical immunotherapy with BCG [3].

A renaissance in the interest of urinary markers has recently been witnessed by a proliferation of publications in the field. These urinary markers may serve in the diagnostic as well as in the follow-up setting, allowing a more rationale use of cystoscopy. While urine cytology and FISH or immunocytology as reflex test are currently the only approved urinary test, newer markers using panels of markers of RNA expression or methylation are under development. Soria et al. (pp. 577–583) provide a thorough update of what is currently in the pipeline in terms of novel urinary markers for detection, surveillance and prognosis of NMIBC. The conclusion is that while several markers have shown improved sensitivity over urine cytology, a validation of their clinical utility is still pending.

In addition to urinary markers, tissue markers are an important avenue whereby we can study the various aspects of tumor biology, appropriately assign risks to patients and provide them with personalized therapies. In their review, Bruchbacher et al. (pp. 584–590) recognize that there is a paucity of validated markers in NMIBC and that there remains an unmet need for improving the accuracy of current prognostic and predictive models, which rely only on clinicopathologic features and do not reflect the biological heterogeneity of the cancer in each individual.

One of the most impressive developments in bladder cancer pertain the technological advances in the field of cystoscopy and technique of TURBT. Combining improved visualization with new resection techniques will likely optimize the diagnostic and prognostic value of TURB at a point that the need of procedures like re-TURB may be reduced. Babjuk et al. (pp. 591–597) are asked to position the clinical value of new enhancement technologies such as narrow band imaging, photodynamic diagnosis and Professional Image Enhancement System based on the available evidence. En block resection has recently been proposed as a new technique to avoid tumour fragmentation and improve specimen orientation; whereas, bipolar TURB aims to reduce complications of the procedure. Purpose of the review by Babjuk et al. is to critically assess whether these new techniques hold the premises to improve the quality of TURB.

Clearly, although clinical questions abound, our ability to effectively manage patients is helped immensely by advances in the field of tumor biology [3]. Here, Dyrskjøt and Ingersoll (pp. 598–603) effectively summarize how recent genomic studies by TCGA and others have revealed that NMIBC possess complexity that can be defined by specific gene expression signatures and has helped to define subsets within this disease. These subsets possess different risk profiles that may impact treatment decisions. Furthermore, in addition to the baseline immunological milieu, the posttreatment response may help to inform whether a specific NMIBC subset is likely to progress. These findings elucidating the molecular landscape of NMIBC will help stratifying patient risk within this disease as well as establish novel or targeted treatment strategies.

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Financial support and sponsorship

A.M.K. is supported by the Wayne B. Duddlesten Professorship in Cancer Research

PG: none.

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Conflicts of interest

A.M.K. serves on advisory board and/or receives trial support from Merck, BMS, FKD, Theralase, Abbott Molecular, MDxHealth, Arquer Diagnostics.

P.G. has been a lecturer and/or attendee in advisory boards for Arquer Diagnostic, Ipsen, Janssen, Cepheid.

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1. Kamat AM, Witjes JA, Brausi M, et al. Defining and treating the spectrum of intermediate risk nonmuscle invasive bladder cancer. J Urol 2014; 192:305–315.
2. Gontero P, Sylvester R, Pisano F, et al. Prognostic factors and risk groups in T1G3 nonmuscle- invasive bladder cancer patients initially treated with Bacillus Calmette-Guerin: results of a retrospective multicenter study of 2451 patients. Eur Urol 2015; 67:74–82.
3. Kamat AM, Hahn NM, Efstathiou JA, et al. Bladder cancer. Lancet 2016; 388:2796–2810.
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