Please also verify that the expansion of HGT1 is OK as set: The risk of progression for high-grade T1 (HGT1) cancer has been recently established at 21% using updated information on large series and a meta-analysis. These outcomes are better than those classically expected supporting the rule of thirds for HGT1. The main limitation of this subgroup is that most studies are retrospective observational studies, which, compared with randomized controlled trials, are subject to various selection biases, carrying a higher risk of uncontrolled confounding factors, with potential preferential reporting of positive findings.
Key points
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Advanced age (≥70 years), female sex, larger tumor size, and multiple tumors are associated with increased progression and, for some of these factors, also decreased cancer-specific survival. Bacillus Calmette-Guérin has also been shown to impact progression and also recently on cancer-specific survival.
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Updated information on large series and a meta-analysis has helped set the risk of progression in 20% of high-grade T1 cases.
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Deep lamina propria invasion combined with age, tumor size, associated carcinoma in situ and other risk factors described should be used for patient stratification in future clinical trials. Future research should attempt to combine these prognostic factors into a risk-prediction nomogram in which validation in a prospective cohort would also be of value.
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Identifying that 20% of patients with risk of progression would allow to indicate selectively both repeat transurethral resection and early cystectomy, preserving bladders in less-risk cases.
Introduction
Approximately 75% of the 386,000 new cases of bladder cancer diagnosed worldwide annually are nonmuscle invasive bladder cancer (NMIBC). In the United States, there are currently 500,000 survivors of bladder cancer, mainly of this NMIBC subtype. It is still unclear what clicks the progression and makes 20% of high-risk NMIBC progress to an invasive and extremely aggressive tumor. Expert recommendations on the optimal treatment strategy for patients within this category range from conservative therapy to early radical cystectomy. There is a strong claim to reexamine the treatment algorithm for these patients, to improve risk stratification, and to find the tools to identify this 20% with the potential of invasiveness.
The first issue to overcome when addressing high-risk bladder cancer is the mere definition of this category. There is no consensus among guidelines as to the risk-level definitions. As a consequence, an international committee of experts on bladder cancer management, the International Bladder Cancer Group (IBCG), reviewed all of these guidelines and published in 2008 and updated in 2011 their take on these variations. Their recommendation was to include as high-risk NMIBC any T1, G3, and/or carcinoma in situ (CIS). Originally, the European Association of Urology’s (EAU) guidelines (2001) included as high-risk NMIBC all T1, G3 (multifocal or highly recurrent), and CIS. With the introduction of the European Organization for Research and Treatment of Cancer’s (EORTC) risk tables, an attempt was made in the 2011 version of the guidelines to use the risk calculator. Currently, the definition of high-risk NMIBC for this association has, in part, gone back to the original definition and considers any of the following to be a high-risk NMIBC: T1 tumor or G3 (high grade) tumor or CIS, together with any multiple, recurrent, and large (>3 cm) Ta G1G2 tumors, if all conditions are present. This definition is quite similar (though not exact) to the definition recommended by the IBCG and, as in that case, involves using the old World Health Organization’s (WHO) grading system (G1, G2, G3) instead of the updated high and low grade.
Throughout the past 2 decades, the variability in the definition of risk levels, together with the changes in the WHO’s grading system and the staging system, has introduced elements of bias. Besides, there are variations in definitions of outcomes or prognostic factors, which might also lead to heterogeneity. Finally, there is a lack in the literature of randomized data and large studies for HGT1 bladder cancer since the advent of bacillus Calmette-Guérin (BCG) in the early 1990s. Most of these studies are retrospective observational studies, which, compared with randomized controlled trials, are subject to various selection biases, carrying a higher risk of uncontrolled confounding factors, with potential preferential reporting of positive findings.
Regardless of the definition used, the clinical care of high-risk NMIBC is directed at preventing progression to muscle invasion because this event marks a dramatic increase in the risk of metastasis and disease-specific mortality. This is as opposed to low- and intermediate-risk NMIBC, for which the focus is on cost and quality-of-life issues. In this update, to keep a focus on progression, prognostic factors, and treatment strategies, the authors use the more restricted definition of high-risk NMIBC contemplating only HG cases, mainly HGT1 and CIS, as well as the more rare case of HGTa.
Introduction
Approximately 75% of the 386,000 new cases of bladder cancer diagnosed worldwide annually are nonmuscle invasive bladder cancer (NMIBC). In the United States, there are currently 500,000 survivors of bladder cancer, mainly of this NMIBC subtype. It is still unclear what clicks the progression and makes 20% of high-risk NMIBC progress to an invasive and extremely aggressive tumor. Expert recommendations on the optimal treatment strategy for patients within this category range from conservative therapy to early radical cystectomy. There is a strong claim to reexamine the treatment algorithm for these patients, to improve risk stratification, and to find the tools to identify this 20% with the potential of invasiveness.
The first issue to overcome when addressing high-risk bladder cancer is the mere definition of this category. There is no consensus among guidelines as to the risk-level definitions. As a consequence, an international committee of experts on bladder cancer management, the International Bladder Cancer Group (IBCG), reviewed all of these guidelines and published in 2008 and updated in 2011 their take on these variations. Their recommendation was to include as high-risk NMIBC any T1, G3, and/or carcinoma in situ (CIS). Originally, the European Association of Urology’s (EAU) guidelines (2001) included as high-risk NMIBC all T1, G3 (multifocal or highly recurrent), and CIS. With the introduction of the European Organization for Research and Treatment of Cancer’s (EORTC) risk tables, an attempt was made in the 2011 version of the guidelines to use the risk calculator. Currently, the definition of high-risk NMIBC for this association has, in part, gone back to the original definition and considers any of the following to be a high-risk NMIBC: T1 tumor or G3 (high grade) tumor or CIS, together with any multiple, recurrent, and large (>3 cm) Ta G1G2 tumors, if all conditions are present. This definition is quite similar (though not exact) to the definition recommended by the IBCG and, as in that case, involves using the old World Health Organization’s (WHO) grading system (G1, G2, G3) instead of the updated high and low grade.
Throughout the past 2 decades, the variability in the definition of risk levels, together with the changes in the WHO’s grading system and the staging system, has introduced elements of bias. Besides, there are variations in definitions of outcomes or prognostic factors, which might also lead to heterogeneity. Finally, there is a lack in the literature of randomized data and large studies for HGT1 bladder cancer since the advent of bacillus Calmette-Guérin (BCG) in the early 1990s. Most of these studies are retrospective observational studies, which, compared with randomized controlled trials, are subject to various selection biases, carrying a higher risk of uncontrolled confounding factors, with potential preferential reporting of positive findings.
Regardless of the definition used, the clinical care of high-risk NMIBC is directed at preventing progression to muscle invasion because this event marks a dramatic increase in the risk of metastasis and disease-specific mortality. This is as opposed to low- and intermediate-risk NMIBC, for which the focus is on cost and quality-of-life issues. In this update, to keep a focus on progression, prognostic factors, and treatment strategies, the authors use the more restricted definition of high-risk NMIBC contemplating only HG cases, mainly HGT1 and CIS, as well as the more rare case of HGTa.
Prognostic factors
Classically, around 30% of these tumors have been considered to progress, with this being part of the currently outdated rule of thirds for HGT1. A new lower cutoff of 21% has been established in a meta-analysis based on more than 12,000 HGT1 cases, consistent with a previous review of high-risk NMIBC based on 3088 patients from 19 trials and a recent multicenter study of 2451 HGT1 cases. Compared with other HGT1 reports with higher progression estimates of up to 40%, this lower rate may represent true improvements in HGT1 prognosis over time and, in part, may also reflect a shift in the definition mentioned in the earlier section. Along the same line, the rates of mortality for this group of bladder cancer were reported to reach 34% ; but these recent reports show a 9% to 14% mortality, with 79% of patients retaining their bladders.
These favorable outcomes confirm that most HGT1 tumors can be safely managed conservatively with standard treatment with first-line BCG. Prognostic factors that might aid in the identification of 20% of HGT1 tumors at higher risk of progression and hence those would benefit most from a repeat transurethral resection (reTUR) and/or an early radical cystectomy are desperately needed. Unfortunately for high-risk NMIBC, the predictive value of the EORTC and club urológico español de tratamiento oncológico (CUETO) scoring systems has been shown to be limited with poor discriminating ability, limited predictive value, and a tendency to overestimate progression.
Pathologic Prognostic Factors
The depth/extent of invasion is the basis of all TNM classification; the importance of substaging results to prognosis in HGT1 disease is a risk factor proposed almost 20 years ago, with more than 2500 published cases substaged according to invasion of the muscularis mucosae. Martin-Doyle and colleagues’ meta-analysis identified deep lamina propria invasion as having the largest negative impact in both progression and cancer specific survival (CSS) in HGT1. Because this evaluation is subject to interobserver and intraobserver variability, it has faced this criticism for the last 2 decades; but there is growing evidence on its reproducibility. Additional work is needed to identify the optimal method to quantify the depth of invasion because other methods for substaging HGT1 that is not yet externally validated have been described.
CIS is also a strong and independent prognostic factor, showing a hazard ratio of 1.24 (confidence interval 1.09–1.4) to a 2-fold increase in the risk of progression. This prognostic factor is limited by the fact that CIS is a microscopic lesion with an incidence in large series around 24%. Its diagnosis can be optimized by additional random bladder biopsies, increasing the incidence to up to 65%.
The involvement of the prostatic urethra and ducts by CIS in male patients with NMIBC has been reported; the risk is higher if the tumor is located on the trigone or bladder neck, in the presence of bladder CIS, and in multiple tumors. In these cases and when cytology is positive with no evidence of tumor in the bladder or when abnormalities of prostatic urethra are visible, loop biopsies of the prostatic urethra are recommended.
The presence of lymphovascular invasion also significantly predicts outcomes (ref WMD ), but the incidence is relatively low (under 15%); further work has to be done to strengthen the evidence. Finally, when micropapillary histology has evaluated specifically within HGT1, it has not been found to carry a significant effect on either recurrence or progression. But this was based on only 2 identified studies meeting the criteria of at least 75 cases of HGT1 and at least 75% of HGT1. Given the conflicting findings on the impact of micropapillary histology, the association of this factor with the prognosis deserves further evaluation, specifically in the HGT1 population.
Clinical Prognostic Factors
The recent report by Gontero and colleagues proposes the combination of age of 70 years and older, size of 3 cm or greater, and the presence of CIS as the highest risk of progression, reaching 52% within this group compared with 17% in the group without any of the 3 risk factors. Advanced age (≥70 years) has been associated with a higher bladder cancer–related mortality and suggests that BCG may be less effective in elderly patients. However, other reports point to advancing age (>70 years) as being associated with a statistically significant lower hazard of progression in HGT1.
Female sex was found to increase the risk of progression but not recurrence or cancer-specific survival by Martin-Doyle and colleagues and Gontero and colleagues, but additional data may be required to confirm this finding. The underlying factors driving this sex disparity are poorly understood and have been hypothesized to include hormonal, anatomic, and societal factors, including sex differences in the immunologic response to BCG.
Both larger tumor size and multiple tumors are associated with an increased recurrence and progression and decreased cancer-specific survival, which is consistent with these factors’ relevance in the broader NMIBC population.
In the broader bladder cancer population, recurrent tumors have also been found to impact negatively when compared with the initial tumor ; but this finding has yet to be confirmed in the restricted group of HGT1.
BCG has a known impact on progression and also recently on cancer-specific survival in HGT1 disease. Maintenance BCG also seems to have a significant positive impact on all outcome measures, strengthening the evidence base for existing recommendations to use BCG in high-risk NMIBC. Besides, the response to BCG has been known for a long time to predict progression .
Chromosomal Alterations and Molecular Markers
Because clinical and pathologic variables alone are inadequate to predict progression in HGT1 bladder cancer, the search for tissue-based biomarkers is an ongoing area of effort even though no marker has been validated thus far. Recent evidence suggests that histopathologic classification into pTa, pT1a, and pT1b can be translated into a molecular signature, reflecting progressive deregulation to more invasive stages.
Altered protein expression of p53, p21, pRb, and p27 has been shown to correlate negatively with outcomes. The value of p53 expression as a prognostic factor in T1G3 disease, however, is controversial. There has also been several articles reporting the ability of microRNAs to help evaluate patients with NMIBC, even though future work is needed to validate the potential clinical utility. Also, the epidermal growth factor receptor as well as the cell cycle regulators, including cyclin D1, cyclin D3, and p53, may have therapeutic importance in T1G3 disease.
Another interesting approach is the search for markers of the BCG response, such as ezrin or cathepsin E, maspin, Plk1, and survivin. All of these markers have been shown to predict progression in a wider population of NMIBC and are in the process of being externally validated in the near future.
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Management of Low-risk and Intermediate-risk Non–Muscle-invasive Bladder Carcinoma
First-Line Treatment and Prognostic Factors of Metastatic Bladder Cancer for Platinum-Eligible Patients
First-line Treatment of Metastatic Disease
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