Elsevier

The Lancet

Volume 388, Issue 10061, 3–9 December 2016, Pages 2796-2810
The Lancet

Seminar
Bladder cancer

https://doi.org/10.1016/S0140-6736(16)30512-8Get rights and content

Summary

Bladder cancer is a complex disease associated with high morbidity and mortality rates if not treated optimally. Awareness of haematuria as the major presenting symptom is paramount, and early diagnosis with individualised treatment and follow-up is the key to a successful outcome. For non-muscle-invasive bladder cancer, the mainstay of treatment is complete resection of the tumour followed by induction and maintenance immunotherapy with intravesical BCG vaccine or intravesical chemotherapy. For muscle-invasive bladder cancer, multimodal treatment involving radical cystectomy with neoadjuvant chemotherapy offers the best chance for cure. Selected patients with muscle-invasive tumours can be offered bladder-sparing trimodality treatment consisting of transurethral resection with chemoradiation. Advanced disease is best treated with systemic cisplatin-based chemotherapy; immunotherapy is emerging as a viable salvage treatment for patients in whom first-line chemotherapy cannot control the disease. Developments in the past 2 years have shed light on genetic subtypes of bladder cancer that might differ from one another in response to various treatments.

Introduction

Each year, bladder cancer is diagnosed in about 74 000 patients in the USA and in more than 430 000 patients worldwide, making it the fourth most common cancer in men and the 11th most common cancer in women.1 However, even though bladder cancer is common, it is often mismanaged. A 2012 analysis of Surveillance, Epidemiology, and End Results Program data suggested that of 4790 patients with high-grade non-muscle-invasive disease diagnosed between 1992 and 2002, only one patient received treatment according to formal recommendations.2 To promote improved adherence to best practices for bladder cancer treatment, we present a state-of-the-art, updated review of diagnosis and management of this disease.

Section snippets

Overview

Most bladder cancers are urothelial carcinomas. At presentation, roughly 75% of patients have non-muscle-invasive bladder cancer and 25% have muscle-invasive or metastatic disease. About 50% of non-muscle-invasive bladder cancers are low grade, whereas most muscle-invasive or metastatic tumours are high grade.3 Morphologically, bladder tumours can be divided into papillary, solid, and mixed types. The papillary type is predominant, especially in non-muscle-invasive bladder cancer.

Grading of urothelial carcinoma

In

Histological variants of urothelial carcinoma

Although urothelial carcinoma accounts for most bladder cancers, other histological types can also be found in the bladder, albeit at far lower frequencies.6, 20 Urothelial carcinomas frequently undergo divergent differentiation, resulting in a wide range of histological variants.6, 21, 22 These histological variants are generally not limited to the bladder; they can also be present in other sites. Therefore, when a histological variant is encountered in the bladder, metastasis from other

Papillary and non-papillary disease

Bladder tumours can be categorised as papillary or non-papillary on the basis of distinct genetic alterations, the most notable of which are activating mutations in FGFR3 in papillary tumours and inactivating mutations involving major tumour suppressors TP53 and RB1 in non-papillary tumours.41 More recently, in 2014, The Cancer Genome Atlas (TCGA)42 and other groups43, 44, 45, 46, 47, 48 have identified additional mutations that distinguish papillary and non-papillary bladder cancers. Both

Clinical presentation

Most patients with bladder cancer are diagnosed during diagnostic testing prompted by haematuria. Visible haematuria is one of the symptoms most strongly correlated with bladder cancer diagnosis; 3 year positive predictive values are 7·4% (95% CI 6·8–8·1) in men and 3·4% (2·9–4·0) in women.66 Patients without haematuria typically have a longer time from onset of symptoms (eg, urgency or recurrent infections) to diagnosis.67 At presentation, most patients present with a solitary lesion smaller

Risk stratification

Reported 5 year rates of non-muscle-invasive bladder cancer recurrence range from 50% to 70%, and reported 5 year rates of progression range from 10% to 30%. Factors associated with recurrence and progression include high stage, high grade, large tumour size, multifocality, high number of previous recurrences, and presence of concomitant carcinoma in situ.86, 87, 88, 89 Other negative prognostic factors include the presence of lymphovascular invasion, histological variants (eg, micropapillary

Radical cystectomy and pelvic lymphadenectomy

Radical cystectomy and bilateral pelvic lymphadenectomy, often preceded by neoadjuvant cisplatin-based chemotherapy, is the gold-standard definitive surgical treatment for bladder cancer.111, 112 Although nerve-sparing radical cystectomy is appropriate in men and women, except when sparing nerves would compromise tumour control (eg, in patients with T3–T4 [advanced] tumours),113 the long-term safety of prostate or seminal vesicle sparing (proposed to optimise sexual function and continence), or

Bladder-sparing trimodality treatment

Patients who want to preserve their native bladder could be candidates for bladder-sparing trimodality treatment, which consists of visibly complete transurethral resection followed by conformal radiotherapy and concurrent radiosensitising chemotherapy (figure 4).134 This approach is supported by completed prospective trials and international consensus guidelines.111, 135, 136, 137

Trimodality treatment for non-muscle-invasive bladder cancer

For Ta or Tis (flat in situ) tumours, trimodality treatment is generally not supported by available evidence. In T1

Muscle-invasive bladder cancer standards of care

The key systemic treatment regimens for muscle-invasive bladder cancer are summarised in table 2.144, 145, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172 At present, the data supporting a benefit for chemotherapy are strongest for neoadjuvant chemotherapy before radical surgery or radiotherapy; data for adjuvant chemotherapy are less robust. In the neoadjuvant setting, cisplatin-based regimens, including MVAC and CMV (cisplatin, methotrexate, and vinblastine), have shown

Follow-up after treatment of urothelial carcinoma

Surveillance for bladder cancer is important because of the high rate of recurrence of both non-muscle-invasive and muscle-invasive disease and the short time to progression and death in patients with metastatic disease. Surveillance strategies are driven by the stage and grade of the tumour and are designed to minimise overtesting while optimising early detection of recurrences.

For non-muscle-invasive bladder cancer, the risk of recurrence after 5 years ranges from 50% to 90%, with higher

Controversies and uncertainties and outstanding research questions

Bladder cancer is a complex disease, and its biology has only begun to be understood. Further research into urinary markers for diagnosis is needed. However, for maximum positive effect on patient care, research should focus on response prediction and monitoring patients during treatment rather than diagnostic evaluation of haematuria. An example of a tool for response prediction is the CyPRIT (Cytokine Panel for Response to Intravesical Therapy), which could potentially allow for real-time

Search strategy and selection criteria

We searched MEDLINE, PubMed, and the Cochrane Library for manuscripts published in English from database inception to Aug 31, 2015. We searched for all articles with the search terms “urothelial carcinoma” or “bladder cancer” in combination with any of the following terms: “epidemiology”, “genetics”, “pathophysiology”, “diagnosis”, “urinary markers”, “biopsy”, “treatment”, “surgery”, “radiation therapy”, “chemotherapy”, “medical therapy”, “chemoradiation”, “trimodality therapy”,

References (183)

  • E Compérat et al.

    Micropapillary urothelial carcinoma of the urinary bladder: a clinicopathological analysis of 72 cases

    Pathology

    (2010)
  • BJ Linder et al.

    Outcomes following radical cystectomy for nested variant of urothelial carcinoma: a matched cohort analysis

    J Urol

    (2013)
  • F Dayyani et al.

    Plasmacytoid urothelial carcinoma, a chemosensitive cancer with poor prognosis, and peritoneal carcinomatosis

    J Urol

    (2013)
  • RR Ricardo-Gonzalez et al.

    Plasmacytoid carcinoma of the bladder: a urothelial carcinoma variant with a predilection for intraperitoneal spread

    J Urol

    (2012)
  • SP Lynch et al.

    Neoadjuvant chemotherapy in small cell urothelial cancer improves pathologic downstaging and long-term outcomes: results from a retrospective study at the MD Anderson Cancer Center

    Eur Urol

    (2013)
  • A Abd El-Latif et al.

    The sensitivity of initial transurethral resection or biopsy of bladder tumor(s) for detecting bladder cancer variants on radical cystectomy

    J Urol

    (2013)
  • RB Shah et al.

    Variant (divergent) histologic differentiation in urothelial carcinoma is under-recognized in community practice: impact of mandatory central pathology review at a large referral hospital

    Urol Oncol

    (2013)
  • MB Amin et al.

    ICUD-EAU International Consultation on Bladder Cancer 2012: Pathology

    Eur Urol

    (2013)
  • DE Hansel et al.

    Challenges in the pathology of non-muscle-invasive bladder cancer: a dialogue between the urologic surgeon and the pathologist

    Urology

    (2013)
  • CP Dinney et al.

    Focus on bladder cancer

    Cancer Cell

    (2004)
  • Y Allory et al.

    Telomerase reverse transcriptase promoter mutations in bladder cancer: high frequency across stages, detection in urine, and lack of association with outcome

    Eur Urol

    (2014)
  • CD Hurst et al.

    Comprehensive mutation analysis of the TERT promoter in bladder cancer and detection of mutations in voided urine

    Eur Urol

    (2014)
  • D Theodorescu et al.

    Telomerase in bladder cancer: back to a better future?

    Eur Urol

    (2014)
  • A Biton et al.

    Independent component analysis uncovers the landscape of the bladder tumor transcriptome and reveals insights into luminal and basal subtypes

    Cell Rep

    (2014)
  • W Choi et al.

    Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy

    Cancer Cell

    (2014)
  • DJ McConkey et al.

    New insights into subtypes of invasive bladder cancer: considerations of the clinician

    Eur Urol

    (2014)
  • FH Groenendijk et al.

    ERBB2 mutations characterize a subgroup of muscle-invasive bladder cancers with excellent response to neoadjuvant chemotherapy

    Eur Urol

    (2016)
  • ER Plimack et al.

    Defects in DNA repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer

    Eur Urol

    (2015)
  • JE Rosenberg et al.

    Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial

    Lancet

    (2016)
  • DJ McConkey et al.

    Therapeutic opportunities in the intrinsic subtypes of muscle-invasive bladder cancer

    Hematol Oncol Clin North Am

    (2015)
  • CH Bangma et al.

    Outcomes of a bladder cancer screening program using home hematuria testing and molecular markers

    Eur Urol

    (2013)
  • M Burger et al.

    Photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data

    Eur Urol

    (2013)
  • Y Lotan et al.

    Sensitivity and specificity of commonly available bladder tumor markers versus cytology: results of a comprehensive literature review and meta-analyses

    Urology

    (2003)
  • E Xylinas et al.

    Urine markers for detection and surveillance of bladder cancer

    Urol Oncol

    (2014)
  • BJ Schlomer et al.

    Prospective validation of the clinical usefulness of reflex fluorescence in situ hybridization assay in patients with atypical cytology for the detection of urothelial carcinoma of the bladder

    J Urol

    (2010)
  • AM Kamat et al.

    Use of fluorescence in situ hybridization to predict response to bacillus Calmette-Guérin therapy for bladder cancer: results of a prospective trial

    J Urol

    (2012)
  • S Cambier et al.

    EORTC nomograms and risk groups for predicting recurrence, progression, and disease-specific and overall survival in non-muscle-invasive stage Ta-T1 urothelial bladder cancer patients treated with 1–3 years of maintenance bacillus Calmette-Guerin

    Eur Urol

    (2016)
  • P Gontero et al.

    Prognostic factors and risk groups in T1G3 non-muscle-invasive bladder cancer patients initially treated with Bacillus Calmette-Guérin: results of a retrospective multicenter study of 2451 patients

    Eur Urol

    (2015)
  • DL Willis et al.

    Clinical outcomes of cT1 micropapillary bladder cancer

    J Urol

    (2015)
  • AM Kamat et al.

    Defining and treating the spectrum of intermediate risk nonmuscle invasive bladder cancer

    J Urol

    (2014)
  • RT Divrik et al.

    The effect of repeat transurethral resection on recurrence and progression rates in patients with T1 tumors of the bladder who received intravesical mitomycin: a prospective, randomized clinical trial

    J Urol

    (2006)
  • A Guevara et al.

    The role of tumor-free status in repeat resection before intravesical bacillus Calmette-Guerin for high grade Ta, T1 and CIS bladder cancer

    J Urol

    (2010)
  • JP Sfakianos et al.

    The effect of restaging transurethral resection on recurrence and progression rates in patients with nonmuscle invasive bladder cancer treated with intravesical bacillus Calmette-Guérin

    J Urol

    (2014)
  • HW Herr

    The value of a second transurethral resection in evaluating patients with bladder tumors

    J Urol

    (1999)
  • RJ Sylvester et al.

    Systematic review and individual patient data meta-analysis of randomized trials comparing a single immediate instillation of chemotherapy after transurethral resection with transurethral resection alone in patients with stage pTa-pT1 urothelial carcinoma of the bladder: which patients benefit from the instillation?

    Eur Urol

    (2016)
  • E Kaasinen et al.

    Factors explaining recurrence in patients undergoing chemoimmunotherapy regimens for frequently recurring superficial bladder carcinoma

    Eur Urol

    (2002)
  • M Huncharek et al.

    Intravesical chemotherapy prophylaxis in primary superficial bladder cancer: a meta-analysis of 3703 patients from 11 randomized trials

    J Clin Epidemiol

    (2000)
  • Cancer facts and figures 2015

    (2015)
  • K Chamie et al.

    Quality of care in patients with bladder cancer: a case report?

    Cancer

    (2012)
  • H Moch et al.

    Tumours of the urinary tract

  • Cited by (1002)

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