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Bladder cancer is the seventh most fre-quent cancer on male population and eleventh within the whole inhabitants. Differences in incidence and mor-tality between countries and regions exist.Those differences depend on variables including ep-idemiological data, social and cultural features and economics amongst the several populations that are ex-posed to different risk factors and treatment approaches. Smoking is the strongest risk factor for bladder cancer, representing approximately 50% of the cases. Its alter-native, the electronic cigarette does not seem to provide a decrease in risk of bladder cancer. Employment expo-sure to aromatic amines, aromatic polycyclic hydrocar-bons and chlorate hydrocarbons, are still important risk factors.Water consumption with high levels of arsenic has also shown an increased risk of bladder cancer. Fast acetyl-ators or genetic predisposition would be tentative risk factors. Some medical treatments with chemotherapy o radiation therapy increase bladder cancer risk. Identi-fying all these factors allows for progress in the field of prevention and early detection. The main objective is to decrease incidence and mortality related to bladder cancer.
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Therapeutic approaches for treatment of urothelial transitional cell carcinoma based on immune system modulation, as well as the contribution of intra-vesical Bacillus de Calmette-Guérin (BCG) and the re-cent incorporation of checkpoint inhibitors had found irrefutable proofs of concept for the indication of antitu-moral immunontherapy in such tumors.Its extension and development at the present time covers all the locations of the wide spectrum of presentation and evolution of these tumors. Nowadays, apart for the low grade non muscle-invasive tumors, we are facing an unpredictable development of antitumoral immuno-therapy in bladder cancer not only as an option in the primary treatment, but also in other scenarios such as non-responders when it comes to BCG, or the situation of ineligibility for systemic chemotherapy indication.The main objective of this review article is trying to trans-late the current basic mechanisms involved in different phases of transitional cell carcinomas antitumoral re-sponse, regardless of whether they are muscle-invasive or not, and to establish the rationale for their therapeutic intravesical or systemic administration.The role of the interactions established between urotheli-al tumor cells and the cellular and molecular elements of the immune system of patients is described, incorporat-ing the relevant and recent advances in immunobiology and the molecular characterization of these tumors that will undoubtedly introduce far-reaching modifications in therapeutic regimes that will contrast with the traditional options available.Investigational lines that are already active in the clinical research phase with BCG and, checkpoints inhibitors of the immune response are also analyzed, highlighting the need to find predictive response markers as a real op-tion for treatments personalization. The approach to the knowledge of the individual reactivity of the immune sys-tem of each patient as a determining factor to achieve it is proposed.
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Bladder cancer was one of the first to have a successful treatment based on immune system stimulation, recognized by patient survival and tumor recurrence data. In addition, bladder tumors are now known to have high antigenic load and are therefore considered to be susceptible to respond well to new immunotherapies. For these reasons, studying the mech-anism of action of bladder cancer immunological-based treatments can provide valuable information both to im-prove their current use and to understand why they work in some patients while others do not tolerate this therapy or have tumor progression.In this article, we will focus on the immune response generated by treatment of non-muscle invasive bladder tumors with BCG, as well as the relationship between this knowledge and new immunotherapies. We will first describe the main activities of the immune system, to continue with the treatment of bladder cancer with BCG, its mechanism of action and biomarkers. Finally, we will summarize the observations that led to the use of monoclonal antibody immunotherapy in cancer and will describe some of the new immunotherapies in use to treat bladder cancer patients.
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Anti CTLA-4, anti PD-L1 and anti PD-1 immune check point inhibitors (ICI) downregulate natural inhibitory pathways of the immune system, in turn increasing tumour surveillance and elimination. Cancer treatment through immune regulation has revolutionised many cancer therapies. However, these new treatments have also brought unique immune related adverse events (irAEs). OBJECTIVE: This paper presents a review of the available knowledge regarding irAE grading, incidence, diagnosis and management, serving as a clinical aid for all clinicians involved with ICI therapy.EVIDENCE ACQUISITION: A comprehensive English-language literature research of original and review articles in the Medline database until June 2020 has been carried out, using the MeSH terms: “immune check point inhibitor toxicities” and “immune related adverse event”.CONCLUSIONS: Further research should aim to investigate if the greater effect of combining ICI treatments is sufficient to justify the increased risk of complications, as well as to identify specific subgroups that will benefit the most from these.
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Since its introduction more than 40 years ago, adjuvant treatment with BCG (Bacillus Calmette-Guérin) for non-muscle invasive bladder cancer (NMIBC) continues to be the treatment recommended in the high-risk group, and one of the most successful immunother-apies for cancer treatment. However, up to 20% of pa-tients will progress to muscle-invasive disease after BCG treatment. On the other hand, we are facing a shortage of BCG supply worldwide. Despite its extensive clinical use, there is no clear certainty of the mechanism of ac-tion of BCG, and controversy persists regarding to the most effective dose and strains, as well as their useful-ness in combined treatments with other drugs and with devices that could facilitate their action on the bladder. This article historically reviews the impact that has had BCG in the treatment of NMIBC, the current guidelines in terms of doses, strains and treatments combination, and the future that will happen with the results of the ongoing clinical trials with systemic immunotherapy, vac-cines and gene therapy.
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BCG is currently the standard of care in intermediate and high risk non-invasive bladder tumors. In high-risk patients treated with BCG up to 30% will re-cur and 10% will progress within 2 years. Oncological outcomes with bladder preserving strategies are limited so radical cystectomy is recommended after BCG failu-re. Some promising treatments, such as checkpoint inhi-bitors (PD1, PDL-1), are being studied for non-responders to BCG. Knowing the management of critical situations during BCG treatment its crucial in daily practice and clinical trials design. The aim of this study is to present these definitions and to remember some important as-pects of BCG management.
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Non-muscle invasive bladder cancer has a high recurrence and progression rate. Endoves-ical administration of chemotherapy after transurethral resection of bladder tumors aims to minimize the recur-rence and progression rates. Over last decades BCG and MMC have been gold standard treatments. Still a large proportion of patients recur and progress. Alto-gether with periods of BCG shortage has facilitate the search for alternatives.In the current manuscript we review the current drugs under study including chemotherapy, immunotherapy and gene therapy. We also updated results on re-cent findings on means of intravesical administration, including hyperthermia assisted by external devices. The objectives of our products are implementing new efficient and safe alternatives and the development of technologies that increase of currently used drugs.After years without improvements in the field, nowa-days we have a myriad of options available. Some of those new devices will remain and reach general urologist for their applicability.Preliminary results are promising and a positive envi-ronment surrounds the urologist in charge of bladder cancer.
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Non-muscle invasive bladder cancer (NMIBC) is a highly heterogeneous disease that hides classes of patients who behave significantly differently under a favorable overall prognosis facade. Individual risk stratification and good decision making improve the patient outcomes. To date, radical cystectomy remains the treatment of choice in particularly aggressive subsets of disease, also due to the lack of proven alternative bladder-sparing strategies.Cancer immunotherapy, by inhibiting the PD-1/PD-L1 axis, has shown durable efficacy in the treatment of advanced and metastatic unresectable urothelial carcinoma, and is studied with great interest in early disease settings. The updated data of the KEYNOTE-057 study have recently promoted the United States (US) Food and Drug Administration (FDA) approval of pembrolizumab in patients with CIS-containing BCG-unresponsive NMIBC. This significant step forward paves the way to a new window of therapeutic opportunities, while underlining new needs and questions to be addressed.
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OBJECTIVES: Bladder cancer is a fre-quent, chemosensitive disease and has shown good out-comes on several chemotherapy regimens over last 60 years. However, very little improvement has been shown in terms of overall survival and side-effects decrease.EVIDENCE ACQUISITION: A review on manuscripts published in English and Spanish from 1949 including the terms chemotherapy and bladder cancer has been performed.EVIDENCE SYNTHESIS: Locally advanced or metastatic bladder cancer chemotherapy was initially introduced for metastasis management. The utilization of cisplatin base regimens has shown superiority over single ther-apy. The most commonly used regimens are cispla-tine-metotrexate-vinblastine, metotrexate-vinblatine-adria-micine-cisplatin y gemcitabine-cisplatin.Neoadjuvant chemotherapy has shown to provide a minimal overall survival advantage, based on level 1 evidence. Neoadjuvant chemotherapy utilizes the same cisplatin-based regimens. Neoadjuvant chemotherapy is underutilized due to the inability to identify non-respond-ers.Adjuvant chemotherapy is more controversial due to the lack of strong evidence. It is used when neoadjuvant chemotherapy has been utilized and the cystectomy pa-thology report is locally advanced. The best outcomes are for low-volume node positive patients.In bladder preservation protocols (aiming to decreased morbidity associated with cystectomy and chemothera-py), several regimens have been utilized in combina-tion with radiation therapy. No standardized treatment is available as no comparisons with cystectomy have been done.CONCLUSION: Chemotherapy has been utilized for several decades in muscle invasive bladder cancer without any major survival improvements or decrease on side-effects. That is the rational why the treatment regimen are widely different amongst groups without a standard treatment.
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INTRODUCTION: With increasing survival from bladder cancer, quality of life, should be one of the main goals following radical cystectomy and bilateral pelvic lymph node dissection (PLND). This technique is associated with significant morbidity, which may have a critical effect on quality of life. Concerns about functional outcomes, such as continence, potency, and sexual function in women, play a role in decision making for urologists and younger patients with muscle-invasive bladder cancer. Several modifications to the classic radical cystectomy technique, include preservation of genital or pelvic organs, developing in the improvement of postoperative continence, potency rates and sexual function in female patients. OBJECTIVE: This review summarizes the organ-sparing cystectomy techniques and its functional and oncological outcomes.EVIDENCE ACQUISITION: A PubMed-based literature search was conducted up to April 2020. We selected the most recent and relevant original articles, metanalysis and reviews that have provided relevant information to guide organ-sparing cystectomy techniques and its functional and oncological outcomes. EVIDENCE SYNTHESIS: In this review, we discuss selection criteria for male and female patients, organ-sparing cystectomy surgical techniques and its functional and oncological outcomes. CONCLUSIONS: Radical cystectomy is associated with significant morbidity, which may have a critical effect on quality of life. Preservation of genital or pelvic organs in men and women, yield better sexual outcomes compared to radical cystectomy without compromising oncological outcomes in well selected patients. But no one of these techniques can be recommended over the classical standard radical cystectomy. Large-scale of prospective and multi-institutional studies are needed to conclude which patients are suitable for these techniques.
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OBJECTIVES: Fifty percent of muscle-invasive bladder cancer (MIBC) patients succumb from metastatic disease despite radical cystectomy (RC). Neoadjuvant chemotherapy (NAC) and adjuvant chemotherapy (ACT) randomized clinical trials (RCT) investigated whether peri-operative chemotherapy improves survival. More recently, immune checkpoint inhibitors (ICI) are explored as peri-operative single agent, ICI-ICI or ICI-chemotherapy combinations. Our goal is to provide the status of neoadjuvant and adjuvant treatment in MIBC.METHODS: The literature on NAC and ACT trials in MIBC was reviewed. RESULTS: Since the 1980s, NAC RCTs were performed in cisplatin-fit patients, mainly using cisplatin combination chemotherapy. Meta-analyses indicated a small, but significant 5% improvement in overall survival in T2-T4N0M0 MIBC patients. Mostly MVAC or gemcitabine-cisplatin (GC) regimens were used without clear benefit of one regimen over the other. NAC value in N+ MIBC is not established and predictive value of associated ~25-40% complete downstaging (pathologically confirmed complete regression, pCR) not unequivocally demonstrated. Adjuvant cisplatin-based chemotherapy RCTs were smaller, some prematurely stopped for poor accrual, and underpowered to demonstrate clear statistical evidence for a 5% overall survival advantage in pT3-T4N1-3M0 MIBC. Novel neoadjuvant immune checkpoint inhibitors, alone or with chemotherapy, phase 2 trials demonstrate downstaging and encouraging clinical results. CONCLUSIONS: Neoadjuvant MVAC or GC in cT2-T4N0 MIBC patients fit for cisplatin is still recommended based on OS benefit shown in meta-analyses, but real-world adherence to NAC is low as ~40-50% of patients are unfit for cisplatin. The value of neoadjuvant treatment in node-positive MIBC is not clearly demonstrated requiring more accurate clinical staging and prospective studies. Adjuvant cisplatin-based chemotherapy may be considered in selected, chemo-naïve pT3-T4N+ patients. Results from prospective checkpoint inhibitor immunotherapy RCTs are needed before immunotherapy becomes a recommended alternative for peri-operative treatment. Molecular tumour subtyping will support selecting novel agents for neoadjuvant or adjuvant strategies.
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Radical cystectomy remains as gold stan-dard for treatment of muscle-invasive bladder cancer. Radical cystectomy has a high morbidity and mortality associated even with the new anesthetic and surgical techniques. Some patients are still not candidates for this major surgery. Besides, some patients reject rad-ical cystectomy. Bladder preservation strategies were develop aiming to decrease morbidity and mortality related to major surgery. Bladder preservation allow for improved quality of life and similar oncologic con-trol rates.Bladder preservation has historically been used in 2 clinical scenarios: 1) Patients unable to undergo a rad-ical cystectomy due to comorbidities o patients that re-ject radical cystectomy, and 2) patients that are offered bladder preservation strategies with and oncological safety and curative intent.This is the real scenario for bladder preservation, the first scenario belongs to palliation, not cure.In the current manuscript, we will review the bladder preservation strategies for muscle invasive bladder cancer, specially focusing on trimodal therapy (recom-mended by international guidelines) and tetramodal therapy.
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OBJECTIVE: Over the last 30 years re-search on metastatic bladder cancer has been slow and limited to chemotherapy. Chemotherapy has provided high initial response rates but very few complete re-sponses that remain overtime. Recently, European med-ical agency has granted approval to immunotherapy in metastatic disease. We will review the clinical trials that drove to EMA approval as well as new promising thera-pies for metastatic bladder cancer.METHODS: A search on PubMed and clinicaltrials. gov through the combination of the following words in English and Spanish was performed: “carcinoma uro-telial”, “cáncer de vejiga”, “localmente avanzado”, “metastásico”, “inmunoterapia”, “CTLA-4”, “PD1”, “PDL-1”, “atezolizumab”, “nivolumab”, “ipilimubab”, “pembrolizumab”, “avelumab”, “durvalumab”, “tremeli-mumab”, “terapia antiangiogénica”, “terapia molecular dirigida” e “inhibidores VEGF”.RESULTS: Cisplatin chemotherapy-based regimens re-main standard treatment for metastatic bladder cancer as per phase III trials. Immunotherapy is available for cisplatin-ineligible patients with high PD-L1 expression, including atezolizumab or pembrolizumab. Trials com-paring immunotherapy, chemotherapy or antiangiogen-ic drugs o targeted drugs are recruiting.CONCLUSIONS: The publication of the comparative studies on chemotherapy and immunotherapy as well as targeted therapy would provide a window of op-portunity for an effective personalized treatment. Those treatment would decrease side-effects as well.
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Until 2016, the treatment options for pa-tients with urothelial carcinoma who had progressed to first line treatment were limited. Vinflunine has been the only approved treatment in Europe for this indication. The only alternatives in these patients were clinical trials or other chemotherapies with low efficacy and high tox-icity. The last couple of years, three immune-checkpoint inhibitors have been approved in Europe (pembroli-zumab, atezolizumab and nivolumab) and five in USA (pembrolizumab, atezolizumab, nivolumab, durvalumab and avelumab), showing improved overall survival (OS), response rate (ORR) and tolerance. Recently, the FDA has approved two new treatments based on the results from the phase II trials. Erdafitinib, the first anti-FGFR treatment in patients with mutations/fusions in FGFR2/3 showed an ORR of 40% and an OS of 13,8 months. Likewise, enfortumab-vedotin, an antibody conjugates, was approved by the FDA based on the phase II trial results. Enfortumab-vedotin presented an ORR of 44% (12% of complete response) and an OS of 11,7 months. Other antiFGFR, antibody conjugates and immunother-apy combinations are in development, with promising results that need to be further confirmed in order to be approved. As a result, the landscape of urothelial can-cer is rapidly evolving. However, the challenge of indi-vidualizing and sequencing treatments remains.
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In the last decades, only few improvements have been made in the comprehension of bladder cancer tumor leading to few improvements in the development of new diagnostic and therapeutic approaches. However, in the last years several step forwards in the field of precision medicine have been made. In this review we focused on some of these elements such as the available biomarkers, the role of enhanced transurethral resection of the bladder and the role of the molecular classification in defining prognosis and therapeutic approaches in bladder cancer patients. Although several progresses have been made, at the time none of the existing biomarkers appear to be able to safely avoid the need of cystoscopy during the follow up of bladder cancer patients. However, these biomarkers represent an important tool to follow up patients with a less invasive methods and in the near future might be able to substitute the need of cystoscopy. Enhanced transurethral resection technique can in some cases reduce the risk of recurrence during follow up, although its impact on survival outcomes is still under debate. Transurethral resection of the bladder represents a fundamental diagnostic and therapeutic step in the management of bladder cancer and these techniques can successfully improve its outcomes. Finally, the molecular classification of the bladder cancer represents one of the most exciting novelty in this field, improving consistently the knowledge of bladder cancer. Improvements regarding prognoses and therapeutics can be achieved although data still need validation.
