Introduction

Approximately 75% of Bladder Cancer (BC) patients present with a non-muscle invasive disease (NMIBC) confined to the mucosa (Ta, CIS) or submucosa (T1). NMIBC represents a heterogeneous disease with different clinical outcomes. These tumors vary from low-grade to very aggressive high-grade disease showing a high risk of recurrence and progression. Thus, an early diagnosis and accurate stratification is necessary to achieve an adequate therapeutic management [1].

Epidemiology

Bladder cancer (BC) is the ninth most common cancer worldwide with a yearly incidence of approximately 430,000 cases in 2012 [2]. BC predominates in males, tobacco smoking and occupational exposure to carcinogens represent the main risk factors [3], however, nowadays the evidence regarding gene-environment interactions is increasing [4].

Non-muscle Invasive Bladder Cancer Pathology

Urothelial tumor staging is crucial, the selection of the treatment, the prognosis and the follow-up scheme depends of an accurate staging. Therefore, staging of BC represent a challenge by the uro-pathologist. According 2016 WHO classification distinguishes pTa, pT1 and pTis are recognize as non-muscle-invasive bladder cancer [5]. pT1 tumors have shown different outcomes according to the depth of invasion, therefore, some studies have divided pT1 tumors into pT1a (invasion above the muscularis mucosae), pT1b (invasion into the muscularis mucosae), and pT1c (invasion under the muscularis mucosae), pT1b-c tumors have shown worse recurrence/progression and cancer-specific survival [6, 7]. Other authors measuring the depth or diameter of the invasive focus divided pT1 tumors as; micro-invasion (T1 m) as a single invasive focus <0.5 mm and T1 extensive-invasive (T1e) as ≥0.5 mm and some studies have suggested that the maximum depth of invasion is associated with tumor recurrence and progression [8]. With regards to the tumor grading, two grading systems coexist, the 1973 WHO and the 2004 WHO/ISUP grading system. While, the EAU guidelines recommends reporting of both the 1973 and 2004 WHO grading systems for NMIBC [1], the AUA guidelines mentions that only the WHO 2004 classification should be used [9]. The WHO 2004 classification system NMIBC was divided into low-grade and high-grade tumors. This modification remains part of the WHO 2016 system, which categorized NMIBC in three categories; papillary urothelial neoplasms of low malignant potential (PUNLMP), noninvasive papillary urothelial carcinoma low-grade (NILGC), and noninvasive papillary urothelial carcinoma high-grade (NIHGC) tumors [5]. The distinction between PUNLMP and NILGC has no major implications in outcomes [10], but the distinction between NILGC and NIHGC tumors show important differences in management and prognosis [11].

Risk Stratification

However, the ability of the EORTC risk tables to estimate the risks of recurrence and progression of patients treated with BCG intravesical instillations were overestimated [15]. The most important pitfalls of all available scoring models are the lead-time bias, secondary to multiple changes in the current standard of treatment, which, cause the scoring models to estimate erroneously the risk of recurrence and progression in patients treated according to current guidelines. Currently, the risk models updated to modern clinical practice are not available, in addition, in the era of precision medicine the optimization of predictive models with the incorporation of new molecular markers (signaling molecules, miRNA and genes expression) is necessary for optimal management.

Diagnosis

Imaging techniques: Currently no imaging modality is sufficiently sensitive for the detection of urothelial carcinoma of the bladder and cystoscopic evaluation of the lower urinary tract is essential in the thorough evaluation of hematuria. The ultrasound (US) represents the first-line imaging investigation of BC in patients with hematuria. A recent study that enrolled 148 patients using US showed; sensitivity, specificity, positive and negative predictive values of 87.1%, 98.1%, 94.4% and 95.4% respectively for BC diagnosis [16], however, the diagnosis performance of US depends of operator experience and the body habitus of the patient. The main advantages of ultrasound are that it does not emit ionizing radiation, is not expensive and is easy to carry out. Contrast-enhanced computed tomography (CT) is the most accurate modality for diagnosis in patients with gross hematuria, commonly CT protocol includes three-phases (unenhanced, nephrographic and excretory phases). The diagnosis performance of CT scan protocol has been evaluated in a study that recruited 435 patients with gross hematuria, 55 patients were diagnosed to BC, the BC detection rate for CT was 87% (48 patients), the sensitivity, specificity, positive and negative values were; 87%, 99%, 91%, and 98%, respectively [17].

Cystoscopy: The white light cystoscopy (WLC) is the current standard of care for the diagnosis of BC. WLC should be performed in all patients with symptoms and/or a suspected BC, it consists in an invasive endoscopic evaluation of the urethra and urinary bladder. WLC can be performed using a rigid or flexible instrument and the urologist should evaluate the entire bladder mucosa surface and describe all the detected lesions (number, size, site and appearance). WLC cannot distinguish benign flat lesions and carcinoma in situ (CIS), and cannot distinguish benign lesions from malignant lesions [1].

Urinary cytology and other urinary markers: The cytological examination of voided urine or washed bladder specimens represents the standard urinary marker in the diagnosis and surveillance of BC. According an accuracy metanalysis the sensitivity and specificity are 37% and 95%, respectively by patients with NMIBC at all stages [18]. However, the diagnostic accuracy in CIS patients shows a better sensitivity (sensitivity and specificity of 87.1% and 63%, respectively) [19]. The Paris System is the standardized terminology and criteria used for urine cytology reporting. The diagnostic categories are: (1) nondiagnostic/unsatisfactory, (2) negative for HGUC (NHGUC), (3) Atypical Urothelial Cells (AUC), (4) suspicious for HGUC (SHGUC), (5) HGUC, (6) Low-grade urothelial neoplasm (LGUN) and (7) secondary malignancies [20]. The United States Food and Drug Administration (FDA) has approved six urinary biomarkers (Bladder Tumor Antigen [BTA] stat, BTA TRAK, nuclear matrix protein [NMP22], and UroVysion, ImmunoCyt, and uCyt) for the diagnosis and surveillance of BC [21]. However, they have not been routinely incorporated in the EAU or AUA guidelines in daily clinical practice. All these markers present a high sensitivity and low specificity, which limit its value as a screening test, however, currently new proteomic, genomic, epigenomic, transcriptomic and metabolomic biomarkers are under investigation.

Optical technologies: Despite the optical quality of new cystoscopes allow a high detection of papillary tumors, the flat lesions and smaller or satellite tumors are important clinical concerns. Therefore, new optical technologies have emerged to improve the detection of BC. Narrow band imaging (NBI) uses the blue (415 nm) and green (540 nm) spectra from white light, these lights are absorbed by hemoglobin, thus highlighting the contrast between capillaries and mucosa. A recent meta-analysis that included 2806 patients show that NBI improve the detection rate of BC; the pooled additional detection rate was 9.9% at all stages, and 25.1% in CIS patients only [22]. Photodynamic diagnosis consists on the intravesical instillation of photosensitizing agents (Hexaminolevulinate or 5-aminolevulinic acid) which accumulated in tumor cells and emit red fluorescence with the exposure to blue light cystoscopy (380–480 nm). The results of a meta-analysis show that PPD improves the detection rate of BC between 9.7–40% in Ta tumors and 3.6–54.5% in T1 tumors, this improvement of the detection rate is higher in CIS patients showing and additional detection rate between 31.9 and 70.6% in this population [23].

Disease Management

Transurethral resection of bladder tumors (TURBT): TURBT is the standard procedure for the diagnosis, staging and treatment of NMIBC. The EAU, AUA and NCCN guidelines on NMIBC recommend complete resection of all visible tumors including sampling of the muscularis propria whenever possible [1, 5, 11]. The difficulty of carrying out a complete resection is reflected in the high rate of residual tumor evident in the literature, which ranges between 17 and 71% for all stages [24]. BC is the most expensive urological malignancy and a high-quality TURBT is critical to correct staging, risk cancer stratification and management [25]. Moreover, there is a growing body of evidence that a complete TURBT is associated with improved NMIBC outcomes [26]. The criteria of a high-quality TURBT do not present a standard definition, however; complete tumor excision with the presence of surrounding normal tissue and muscle layer, register of information for a correct clinical staging and cancer risk stratification and absence of complications have been suggested by some authors as plausible features of a high-quality TURBT [26, 27].Therefore, with the aim of standardized the reporting and TURBT quality improvement, a 10-item checklist (Table 34.2) has been evaluated in clinical practice showing a TURBT improved reporting of critical procedural elements, and enhanced surgeon attention to important aspects of the procedure [27]. In order to increase the quality of the TURBT, the use of new optical technologies has been evaluated. Thus, NBI-TURBT shows to reduce residual disease compared to WLC-TURBT (overall 6.3% vs. 17.5% and primary site 4.2% vs. 13.4%, respectively) [28]. Similarly, PPD has been shown to improve the quality of resection and decrease residual tumor disease [29]. On the other hand, TURBT could be performed using two methods; Conventional TURBT (cTURBT) that consists of standard retrograde excision of the tumor using an electrical wire loop used via a resectoscope [1], this is still the gold standard, these techniques can be performed using monopolar energy, bipolar energy or bipolar plasmakinetics in large tumors [30, 31]. There is a lot of evidence that bipolar energy decreased bladder injury associated with obturator nerve reflex and improve the detrusor sampling without changes in outcomes [30]. However, there are several clinical concerns using cTURBT, such as; multiple tumor fragmentation, risk of tumor cell seeding, high rate of residual disease and missing of detrusor sampling. Therefore, in the last decade, en-bloc resection of bladder tumor (EBRT) has gained acceptance, it can be performed using monopolar and bipolar energy, lasers, or water jet. The main advantages described for the EBRT are; preservation of tumor architecture, improve detrusor sampling and lower risk of complications. To date, ERBT is still under investigation and information on outcomes is missing [32].

Biopsies of suspicious areas of the bladder mucosa, Random biopsies (RBs) and biopsy prostatic urethra: According to the EAU guidelines, all suspected areas should biopsied, Random biopsies should be performed for nonpapillary tumors or when cytology is positive [1]. This recommendation is based on two trials with a very low incidences of positive biopsies (1.5–3.5%) [33]. In a recent meta-analysis that enrolled 10,975 NMIBC patients at all stages who underwent RBs shows a CIS incidence of 17.35%. The authors found a higher incidence of CIS in patients with positive cytology, multiple tumors, nonpapillary tumors, stage T1 tumors, and tumor grade G2/G3, and when the RBs had been performed in a standardized manner according to the EAU guidelines. Based on this data, the authors suggest that RBs should be perform in high-risk and intermediate-risk groups [19]. Prostatic urethral involvement has described as a silent process associated to high-risk tumors [34, 35]. The biopsy of the prostatic urethra is recommended in cases of bladder neck tumor when CIS is present or suspected, when cytology is positive without evidence of tumor, and when abnormalities of the prostatic urethra are visible [1]. Biopsies of the prostatic urethra in the paramontanal zone with a resection loop have been shown to have higher diagnostic performance than cold cup biopsy, allowing characterization of the prostatic urethral mucosa, paraurethral ducts, and stromal invasion [36].

Second-TURBT: According to guidelines, a second-TURBT of bladder tumors within 2–6 weeks after initial resection is indicated when; (1) incomplete first TURBT, (2) absence of detrusor muscle in the initial specimen, (3) clinical suspicion of worse disease than reported by the pathology (4) T1 stage tumors [1]. This recommendation is based on follow issues; (1) high rate of residual disease; (17–67% and 20–71%; for Ta and T1 initial tumors, respectively) and (2) high rate of upstaging; (0–23% and 0–32%; for Ta and T1 initial tumors, respectively) [24]. Second-TURBT reduces the uncertainty of the depth of tumor invasion, permits better control of the initial tumor, and provides additional pathologic information to select the treatment. Despite published data, the impact of second-TURBT on outcome is still controversial, however, recently, Gontero et al. in a cohort of 2451 patients with T1-HG/G3 treated with BCG (935 underwent second-TURBT) show that second-TURBT improved outcomes only when the muscle layer is not present in the initial specimen, these data suggest that second-TURBT could be unnecessary when the muscle layer is present in the initial specimen [37]. Moreover, Palou et al. using the same cohort of patients found that the recurrence rate, progression rate, and cancer-specific mortality is significantly higher in patients with T1 stage at second-TURBT compared to patients with Ta tumors, however, the authors indicated that the pathology at second-TURBT might not be enough to support early radical treatment, based on the fact that 79% of T1G3 patients do not progress during 10-years of follow-up [38].

Intravesical Chemotherapy

Single Immediate Instillation of Chemotherapy After Transurethral Resection: According to EAU and AUA guidelines on NMIBC a single immediate instillation (SII) of chemotherapy after complete transurethral resection of the bladder (TURBT), is recommended in patients with low- or intermediate-risk NMIBC or with small-volume, low-grade Ta NMIBC, respectively [1, 9]. This recommendation is based on an individual patient data meta-analysis that shows a global reduction in recurrence risk by 35%, without changes in progression or mortality. However, SII appears to be not effective in patients with a prior recurrence rate of more than one recurrence per year or in patients with EORTC recurrence risk score >5 [39]. Despite these findings, in daily clinical practice it is difficult to identify patients in whom a SII could be useful at the time of TURBT. There are different chemotherapeutic agents that have shown their effectiveness in RCTs, such as; mitomycin C (MMC), Pirarubicin, Epirubicin, and Gemcitabine, however, there is no consensus regarding which agent presents the best oncological outcomes. Recently, a network meta-analysis of RCTs shows that Pirarubicin, MMC and Epirubicin are the most effective drugs and they decrease tumor recurrence in 69%, 60%, and 38%, respectively [40]. Moreover Messing et al., in a randomized double-blind clinical trial conducted at 23 centers concluded that among patients with suspected low-grade NIMBC, immediate post-resection intravesical instillation of gemcitabine, compared with instillation of saline significantly reduced the risk of recurrence over a median of 4.0 years [41]. Although the use of the SII seems to be rational, its role to improve BC outcome has been questioned. Thus, in a RCTs where 404 patients enrolled to 50 mg Epirubicin versus Placebo the recurrence rate was 51.0% in the Epirubicin group and 62.5% in the placebo group (p = 0.04), overall 63% of the recurrences were between 1 and 5 mm and half of the patients were treated with outpatient fulguration. The authors concluded that SII of chemotherapy only prevents small recurrences which could be treated by fulguration in an outpatient setting and therefore questioned the value of SII of chemotherapy after TURBT [42]. Another clinical concern is the ideal time to perform early instillation, this question still remains unanswered, however, it appears that to perform installations even a few days after TURBT could be acceptable. However, the results of RCTs and meta-analyses support that the use of SII reduces recurrence rate after TURBT in well-selected patients.

Adjuvant chemotherapy: The EAU guidelines recommend 6–12 months of intravesical chemotherapy (or a minimum of 1 year of BCG) following complete TURBT in intermediate risk patients [1]. Since the inclusion of chemotherapeutic instillations in the diary clinical practice, different clinical concerns have arisen, first of all the lack of a standard administration schedule (optimal dose, frequency or duration of such a course and the best chemotherapeutic agent) and secondly the lack of efficacy to prevent or delay the progression of the disease that has been described for treatment with BCG, which could suggest that the initial treatment with BCG could offer better outcomes [43]. Epirubicin, doxorubicin, and MMC are the most studied agents, however, to date there are no studies comparing efficacy between them. Regarding schedules, frequency and duration there are several heterogeneity in RCTs and conflicting evidence has been published. Despite of these issues, the rationale use of chemotherapy after TURBT is based on its ability to reduce the risk of recurrence. Thus, a systemic review on intravesical chemotherapy administered in an adjuvant setting after TURBT showed improvement in short-term (1–3 years) recurrence rate (approximately 20%) [44]. Likewise, Huncharek et al. in a meta-analysis of 11 RCTs that involved 3703 primary tumors patients comparing patients treated with intravesical chemotherapy after TURBT versus TURBT alone shows 44% reduction in 1-year recurrence among patients treated with intravesical chemotherapy versus those treated with TURBT alone [45]. Using the same methodology; Huncharek et al. in another meta-analysis including 1609 patients with recurrent tumors found a 38% reduction in the risk of disease recurrence at 1 year [46]. Although the evidence shows a superior efficacy of BCG compared with chemotherapy due to BCG ability to improve the progression rate, these findings have not been corroborated recently. In that sense, a contemporary individual patient data meta-analysis that included 2820 patients found that BCG with maintenance schedules appears to be better to MMC in reducing the risk of recurrence, however, no statistically significant differences between MMC and BCG were found on progression and survival [47]. Another critical issue is the need for a maintenance schedule, however, published RCTs show contradictory results. The most evidence suggests that there is no significant advantage of maintenance schedule over induction therapy alone in recurrence, progression, or survival [48].

BCG immunotherapy: Intravesical instillation of BCG is the standard therapy for intermediate- and high-risk BC [1, 9, 12]. The absolute efficacy of BCG instillation has been shown in several clinical trials comparing the TURBT plus adjuvant BCG versus TURBT alone and reported an improvement in recurrence, progression and CSS [49], these findings have been corroborated in recent meta-analyses [50]. BCG instillation also has been compared with intravesical chemotherapy.

Thus, an individual patient data meta-analysis (over 2800 patients) of nine randomized studies comparing BCG maintenance showed a 32% reduction in risk of recurrence on BCG compared to MMC without differences in progression and survival [43]. There is a lack of evidence as to which schedule, strains, duration, the timing of administration, doses, frequency of administration, and sequencing of therapy are the most effective. In this sense, the role of the maintenance schedule of BCG therapy is classically supported by the Sylvester et al.’s meta-analysis which involved 24 trials (4863 patients at all stages) showing an overall risk reduction in progression of 27% and this findings has been recently confirmed in a contemporary metanalysis that involved ten RCTs [51]. Although, there is no consensus about most efficient maintenance and schemes vary from one instillation every 3 months during 1 year to 21 instillations given over 3 years has been described, the classical maintenance BCG protocol was established in the Lamm et al. study (induction and 3-week maintenance at 3, 6, 12, 18, 24, 30, and 36 months) based on 384 patients randomized to BCG maintenance therapy versus no BCG maintenance therapy, finding a significant improvement in recurrence-free and progression-free survival of 19% and 6%, respectively in favor to maintenance arm [52]. Regarding the strains, an RCT involving 142 high-risk NMIBC patients comparing two BCG strains (Connaught and Tice) showed that Connaught strains significantly improved 5-year recurrence-free survival compared with treatment with BCG Tice [53]. However, these findings have not been confirmed by a recent network meta-analysis that failed to show a significantly superiority to another BCG strain during direct and indirect comparisons. However, Tokyo 172 strain shows a trend to superiority and should be compared with other strains in a RCT [54]. Side effects are important disadvantages of intravesical BCG treatment. The most studied strategy in order to reduce side effects, is the instillation of low-dose BCG. In this regard, some RCT and metanalysis have been shown that low-dose BCG is not inferior to standard-dose BCG for tumor recurrence and progression, moreover, low-dose BCG appear to reduce overall side effects, especially systemic side effects but no local side effects [55].

Role of early cystectomy in high-grade T1 bladder Cancer: According to clinical practice guidelines, the treatment of choice in patients with high-risk bladder tumors is intravesical instillations of BCG [1, 9, 12], however, it is known that between 23 and 74% have recurrence and even 50% progress during follow-up [56]. It has been described that deferring radical cystectomy presents worse outcomes compared to early cystectomy (5 years CSS; RC before progression (≤pT1) vs. RC after progression during follow-up (≥pT2); 85.4% vs. 52.9%) [57].

However, the ideal timing and the selection of the suitable patient for early radical cystectomy is a challenge, moreover, based on the substantial morbidity of the surgery it could be considered overtreatment. The validation risk stratification tools proposed by EORTC and CUETO group appear to have limited predictive value in patients with high-grade T1 tumors, tending to overestimate progression. A recent retrospective review of 2451 high grade T1 tumor patients was found that age, tumor size, and concomitant carcinoma in situ (CIS) are the most important prognostic factors for progression and propose dividing the patients into four risk groups according to the number of prognostic factors (progression rate of 17.3%, 25.3%, 32.2%, and 52% in patients with zero, one, two, and three progression predictive factors) [58].

Likewise, a meta-analysis that involved a total of 15,215 high-grade T1 tumor patients showed that the depth of invasion into lamina propria (T1b/c) is the most important risk factor for progression. Other factors that also impacted progression and mortality were lymphovascular invasion, concomitant CIS, lack of BCG treatment, tumor size more than 3 cm, and older age.

Despite the optimal management strategy for high-grade T1 tumor patients remain controversial and selection between bladder preservation and radical cystectomy is an important clinical concern in urology, published data can improve the selection criteria of patients undergoing early radical surgery and reducing the risk of over-treatment.

Conclusions and Recommendations

• 
  

  The accurate staging of BC is essential for risk-adapted treatment and follow-up. Risk stratification and prognosis estimation should be performed in NMIBC patients using available scoring models EORTC tables and CUETO scoring model due to prognosis importance.

  
  
• 
  

  The current standard for the diagnosis of BC is white light cystoscopy and cytology, however, it shows that new optical technologies (NBI and PDD) significantly increase the detection rate of BC, although, its use has not been standardized in daily clinical practice.

  
  
• 
  

  TURBT is the standard procedure for the diagnosis, staging, and treatment of NMIBC. High-quality TURBT is a not well-defined concept but it has been suggested that complete tumor excision, correct clinical staging and absence of complications are plausible features.

  
  
• 
  

  The use of an SII of a chemotherapy agent after TURBT has some beneficial effect on BC recurrence and it should be always considered in low-risk patients (EORTC recurrence risk score ≤5).

  
  
• 
  

  Intravesical chemotherapy following complete TURBT is the evidence-based treatment for intermediate-risk BC patients. It has been shown to reduce recurrence risk in both primary and recurrent intermediate-risk tumors without changes in progression.

  
  
• 
  

  Intravesical BCG immunotherapy is standard therapy for intermediate- and high-risk BC. BCG has shown to have superior efficacy compared with chemotherapy due to BCG ability to improve the progression rate in high-risk but not in intermediate-risk patients.

  
  
• 
  

  Early radical cystectomy should be offered in a risk-adapted manner in high-grade T1 tumors with other factors of poor prognosis to improve survival and avoid the risk of overtreatment.

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related posts:

Complexes in Urology of Adult Male Hormonal Disorders Physiology and Pharmacology of the Lower Urinary Tract of Local, Regional, and Metastatic Penile Cancer Staging and Management of Testis Cancer Trauma

Stay updated, free articles. Join our Telegram channel

Join