November 17, 2020 Andrew T. Lenis, MD, MS1; Patrick M. Lec, MD1; Karim Chamie; et
alMD, MSHS1
Author Affiliations Article Information JAMA. 2020;324(19):1980-1991. doi:10.1001/jama.2020.17598
Abstract
Importance Bladder
cancer is a common malignancy in women and is the fourth most common malignancy
in men. Bladder cancer ranges from unaggressive and usually noninvasive tumors
that recur and commit patients to long-term invasive surveillance, to
aggressive and invasive tumors with high disease-specific mortality.
Observations Advanced
age, male sex, and cigarette smoking contribute to the development of bladder
cancer. Bladder tumors can present with gross or microscopic hematuria, which
is evaluated with cystoscopy and upper tract imaging depending on the degree of
hematuria and risk of malignancy. Non–muscle-invasive tumors are treated with
endoscopic resection and adjuvant intravesical therapy, depending on the risk
classification. Enhanced cystoscopy includes technology used to improve the
detection of tumors and can reduce the risk of recurrence. Patients with
high-risk non–muscle invasive tumors that do not respond to adjuvant therapy
with the standard-of-care immunotherapy, bacille Calmette-Guérin (BCG),
constitute a challenging patient population to manage and many alternative
therapies are being studied. For patients with muscle-invasive disease, more
aggressive therapy with radical cystectomy and urinary diversion or trimodal
therapy with maximal endoscopic resection, radiosensitizing chemotherapy, and
radiation is warranted to curb the risk of metastasis and disease-specific
mortality. Treatment of patients with advanced disease is undergoing rapid
changes as immunotherapy with checkpoint inhibitors, targeted therapies, and
antibody-drug conjugates have become options for certain patients with various
stages of disease.
Conclusions and Relevance Improved understanding of the molecular biology and
genetics of bladder cancer has evolved the way localized and advanced disease
is diagnosed and treated. While intravesical BCG has remained the mainstay of
therapy for intermediate and high-risk non–muscle-invasive bladder cancer, the
therapeutic options for muscle-invasive and advanced disease has expanded to
include immunotherapy with checkpoint inhibition, targeted therapies, and
antibody-drug conjugates.
Introduction
Bladder
cancer accounts for an estimated 500 000 new cases and 200 000 deaths
worldwide, and in the US alone there are more than 80 000 new cases and 17 000
deaths each year.1,2 It represents a spectra of
diseases, from recurrent noninvasive tumors managed chronically, to aggressive
or advanced-stage disease that requires multimodal and invasive treatment.
Advances in understanding of the underlying biology of bladder cancer has fundamentally
changed how this disease is diagnosed and treated.
The
objective of this article is to provide an evidence-based review of the
epidemiology, pathophysiology and molecular biology, diagnosis, and management
of bladder cancer. Several guidelines have been published by the American
Urological Association (AUA), the European Association of Urology (EAU), and
the National Comprehensive Cancer Network (NCCN), which will be referenced
herein and provide background information and management recommendations.
Methods
A
literature review was conducted to address the epidemiology, risk factors,
pathophysiology, molecular biology, presentation, diagnosis, and management of
the various forms of bladder cancer. A formal systematic review was not
performed, but relevant literature was identified by searching PubMed for
English-language articles from inception through April 2020. Preference was
given to articles that reported findings from meta-analyses and large
randomized clinical trials (RCTs).
Data
presented regarding management was compiled from the AUA, EAU, and NCCN
guidelines.3-8 The strength of the
recommendation and quality of supporting evidence varies with each organization
and was reported herein as follows: guideline, strength/level of evidence. The
AUA guideline recommendations are “strong,” “moderate,” or “conditional,” based
on A (high), B (moderate), or C (low) levels of evidence. The EAU
recommendations are “strong” or “weak,” and the level of evidence was graded
from 1 (high-quality systematic reviews and individual RCTs) to 5 (expert
consensus), as per the Oxford Center for Evidence-Based Medicine.9 The NCCN recommendations are
“preferred intervention,” “other recommended intervention,” or “useful in
certain circumstances,” based on levels of evidence 1 (high-level evidence and
uniform consensus) to 3 (major NCCN disagreement).
Epidemiology and Risk Factors
Scope
of the Disease
The
lifetime risk of bladder cancer is approximately 1.1% in men and 0.27% in
women.1 Higher incidence is reported in
Western societies, largely due to carcinogen exposure.10 The prevalence of bladder cancer
is high, with more than 1.6 million living with the disease worldwide.1
Risk
Factors
Advanced
age is the greatest risk factor for bladder cancer, with an average age of
diagnosis between 70 and 84 years.11 This is explained by exposure to
carcinogens such as tobacco smoke and, less commonly, benzene chemicals and
aromatic amines, combined with an age-related reduction in the ability to
repair DNA.12 While non-Hispanic White persons
have the highest age-adjusted incidence rates of bladder cancer (23.09 [95%CI,
22.97-23.21] per 100 000 person-years), African Americans have worse
disease-specific outcomes and greater rates of unfavorable pathology.13,14 Men are diagnosed with bladder
cancer with 3 to 4 times the frequency of women, traditionally attributed to
exposures and lifestyle, but stasis of urine-containing carcinogens in men with
prostatic enlargement and urinary retention may also increase risk.12,15 Hematuria in women is often
attributed to infection, resulting in delays in the diagnosis of bladder cancer
and, consequently, worse cancer-specific and overall survival in women.15 Recent studies have demonstrated
the effects of hormone receptors and genomic differences in some bladder
cancers in women compared with men, which may also partially account for
survival differences.16
Cigarette smoking is an important modifiable exposure, with a
population-attributable risk of approximately 50%.17 Occupational exposures include
benzene dyes and factory chemicals. Chronic inflammatory conditions such as
bacterial and Schistosoma hematobium (particularly common in
Northern Africa) infections, chronic indwelling Foley catheters, and prior
bladder augmentation result in increased cellular proliferation predisposing to
urothelial malignancy.18,19 Pelvic radiation (eg, for
prostate, rectal, or cervical cancer) and cyclophosphamide, an alkylating
cytotoxic chemotherapy agent, both increase the risk of bladder cancer.20-25
Epidemiologic
studies have also demonstrated a component of heredity in the development of
urothelial cancer. In a series of more than 200 000 same-sex twin individuals
the estimated percent familial risk was 9.9% for monozygotic twins and 5.5% for
dizygotic twins.26 In a study of nearly 600
patients with bladder cancer, variants in germline DNA, which can result in
inherited risk of bladder cancer, were identified in 14% of patients; 83% of
these variants were in DNA-damage repair genes.27 Lynch syndrome is an example of
an autosomal dominant genetic syndrome caused by a highly penetrable alteration
in DNA mismatch repair genes.28 Among other tumors that may
develop in patients with Lynch syndrome, the lifetime risk of urothelial tumors
of the upper urinary tract is estimated to be 0.4% to 20%.29 Whether the risk of bladder
cancer is increased, however, remains controversial.
Pathophysiology and Molecular Biology
Bladder
cancer is a carcinoma of the urothelial, or “umbrella,” cells that line the
lumen of the urinary bladder. Technically, urothelial carcinoma includes tumors
of the bladder, upper urinary tract (renal pelvis and ureters), and proximal
urethra. Bladder cancer accounts for approximately 90% to 95% of urothelial
carcinoma and is the focus of this review. Histologically, bladder cancer
comprises 75% pure urothelial carcinoma and 25% “variant” histology, adding
complexity to the management of this disease.30
Bladder
cancer can be categorized in several ways. It is classified into high-grade vs
low-grade disease based on standardized histomorphologic features as described
by the World Health Organization. Tumor stage is assigned as a measure of depth
of bladder wall invasion (Table 1). Tumors isolated to the urothelium
(stage Ta) and the lamina propria (stage T1) are considered non–muscle-invasive
bladder cancer (NMIBC) and are treated differently from tumors that invade the
muscle (stage T2) or beyond (stages T3 and T4), called muscle-invasive bladder
cancer (MIBC). Carcinoma in situ (CIS) is a distinct phenotype defined as a
high-grade flat noninvasive lesion with particularly high rates of recurrence
and progression.
Underlying
these phenotypes are genetic alterations at the DNA and subsequent RNA
expression level, forming distinct molecular subtypes that have prognostic,
predictive, and therapeutic implications. Initial insights included the
identification of high mutational burden of bladder cancer, similar to melanoma
and lung cancer, providing a biologic basis for its response to immunotherapy.31 Independent efforts from
multiple groups have identified mutations common in low-grade NMIBC (FGFR3,
PIK3CA, STAG2, RTK/RAS/RAF pathway genes) and high-grade MIBC/advanced
disease (ERBB2, p53, RB1, MDM2, CDKN2A, KDM6A, ARID1A). Tumors may be
categorized into molecular subtypes (eg, luminal, basal/squamous) that inform
clinical behavior such as response to neoadjuvant chemotherapy, sensitivity to
immunotherapy, and risk of progression.32
Presentation and Diagnosis
The
most common presentation of bladder cancer is visible, or gross, hematuria, but
patients can also present with isolated microscopic hematuria (urinalysis
showing ≥3 red blood cells per high-power field), irritative voiding symptoms,
or a tumor incidentally discovered on imaging. The risk of bladder cancer is
approximately 4% in patients with microscopic hematuria and 16.5% in those with
gross hematuria.33 A guideline-recommended workup
is presented in Table 2. Evaluation of gross
hematuria involves visualization of the bladder with cystoscopy and imaging of
the upper urinary tract (ie, kidney, renal pelvis, and ureter) with
cross-sectional urography. Updated microscopic hematuria evaluation guidelines
from the AUA now recommend workup based on the risk of having bladder cancer,
as compared with prior guidelines that indiscriminately recommended
cross-sectional imaging.5 This change reflects the
relatively low frequency of malignancy found on evaluation combined with the
invasive nature of cystoscopy, radiation exposure from cross-sectional imaging,
and the associated health care costs of obtaining these procedures.
Cystoscopy
and Endoscopic Resection
Patients
who may have bladder cancer undergo cystoscopy to evaluate the lower urinary
tract. Cystoscopy is an office-based procedure performed with a flexible camera
approximately 5 mm in diameter inserted via the urethra. Enhanced cystoscopy
with narrow-band imaging or blue light cystoscopy offer improved sensitivity
and specificity for identifying bladder tumors during diagnostic cystoscopy and
endoscopic resection. Narrow-band imaging improves the detection rate
(approximately 10% and 20% on a per-patient and per-lesion basis, respectively)
and decreases the risk of recurrence at 3 and 12 months.34 Blue light cystoscopy detects up
to 14% of papillary Ta/T1 lesions and 40% of CIS lesions missed on conventional
cystoscopy.35
Endoscopic
resection, or transurethral resection of bladder tumor (TURBT), of newly
identified bladder tumors is diagnostic and potentially therapeutic. Its
purpose is 2-fold—to resect all visible tumors and perform disease staging.3 In the case of an incomplete
resection, lack of detrusor muscle in the pathologic specimen, or pathologic
high-risk stage Ta or T1 disease, repeat TURBT is recommended within 4 to 6
weeks. Repeating the TURBT under these circumstances is critical, because there
is a 51% rate of residual disease in patients with T1 disease and an 8% rate of
upstaging from T1 to muscle-invasive disease with repeated procedures.36 Improving TURBT technique is a
focus of quality improvement in bladder cancer care, as evidence links quality
of resection to clinical outcomes.37 A retrospective cohort study of
1865 patients who underwent TURBT for bladder cancer found that an inadequate
staging resection was associated with poorer cancer-specific survival (hazard
ratio [HR], 1.48 [95% CI, 1.00-2.18]).37
Imaging
Cross-sectional
urography (ie, computed tomography or magnetic resonance imaging urogram) is
used to evaluate the upper urinary tract of patients with gross hematuria and
high-risk microscopic hematuria, while renal ultrasound is used in patients
with low- and intermediate-risk microscopic hematuria (Table 2). Although patients suspected of having
bladder cancer are not routinely evaluated with imaging for the purpose of
initial staging, a novel multiparametric system, VI-RADS (Vesical
Imaging-Reporting and Data System), may be used to identify muscle invasive
disease. In a meta-analysis of 6 studies with more than 1000 patients, the
pooled sensitivity and specificity for detection of MIBC was 0.90 (95% CI,
0.86-0.94) and 0.86 (95% CI, 0.71-0.94).38
Urine
Tests and Biomarkers
Urine
cytology is used in the evaluation of gross hematuria and in posttreatment
surveillance. The test involves a pathologist’s survey of sloughed primarily
high-grade malignant urothelial cells, which lose their adhesive properties
more readily than low-grade malignant cells. In a recent meta-analysis, the
pooled sensitivity of urine cytology was 0.37 (95% CI, 0.35-0.39) and pooled
specificity was 0.95 (95% CI, 0.94-0.95).39 While several urine biomarkers
are approved by the US Food and Drug Administration (FDA) and are useful
adjuncts in select patients, all lack the diagnostic accuracy required to
replace cystoscopy.3 Detection of circulating tumor
cells has been associated with clinical outcomes such as cancer-specific
survival (HR, 5.18 [95% CI, 2.21-12.13]) and detection of cell-free tumor DNA
with outcomes such as metastatic relapse (100% sensitivity, 98% specificity).40,41
Management
Non–Muscle-Invasive
Bladder Cancer
NMIBC
represents approximately 70% of organ-confined bladder cancer.42 It comprises a wide spectrum of
disease, and the AUA has stratified patients into low-, intermediate-, and
high-risk categories (Table 3 and Table 4). Although survival is favorable,
patients with low- and intermediate-risk NMIBC experience 5-year
recurrence-free survival rates of 43% and 33%, respectively, and up to 21% with
high-risk disease will progress to MIBC (Box).43,44 Patients with low-risk disease
who undergo a complete initial resection are managed with cystoscopic
surveillance. Patients with high-grade stage Ta (AUA, moderate/C) or T1 (AUA,
strong/B; EAU, strong/2) disease should undergo a repeat resection, given the
risk of understaged or persistent disease in 17% to 67% of stage Ta tumors and
20% to 71% of stage T1 tumors.3,6 Barring upstaging to
muscle-invasive disease on repeat resection, patients with intermediate-risk
(AUA, moderate/B; EAU, strong/1a) and high-risk (AUA, strong/B; EAU, strong/1a)
disease should receive a regimen of intravesical therapy.
Perioperative Chemotherapy
When low- or intermediate-risk disease is suspected, a single
dose of intravesical chemotherapy may be administered within 24 hours of TURBT
with the goal of killing free-floating tumor cells, thereby mitigating seeding
of the urothelium (AUA, moderate/B; EAU, weak/1a).3 A meta-analysis of 7 randomized
trials demonstrated a 39% reduction in the odds of tumor recurrence (absolute
decrease from 48% to 37%) with intravesical chemotherapy at a median follow-up
of 3.4 years.45 Mitomycin C has long been the
agent of choice in this setting, but it is associated with irritative voiding
symptoms and rare bladder necrosis and is expensive.46 More recently, gemcitabine has
emerged as a viable alternative with similar efficacy and improved tolerability
at a lower cost.47 Additional intravesical
chemotherapeutic agents are available, including valrubicin and epirubicin;
however, no randomized data compare efficacy of the above agents with one
another.
Bacille Calmette-Guérin
Bacille Calmette-Guérin (BCG), a live attenuated form of Mycobacterium
bovis, is the preferred treatment for high-risk NMIBC and an option for
intermediate-risk NMIBC. The precise mechanisms by which this form of
immunotherapy exerts its effects are complex. It has been posited that BCG
adheres to the urothelium, is internalized, then induces antigen-presenting,
cell-mediated induction of innate and adaptive immune responses.48 It is instilled into the bladder
for 90 to 120 minutes, once weekly for 6 weeks, during an induction phase. If
the patient tolerates and responds to treatment, as assessed by postinduction
cystoscopy, a maintenance regimen should be continued for 1 year (AUA,
moderate/C for intermediate risk) to 3 years (AUA, moderate/B for high risk).3 Contemporary rates of complete
response are near 80% after induction and are durable at near 55% at 3 years. A
meta-analysis of patients with CIS demonstrated that BCG improved the
recurrence-free rate from 26% to 47% (odds ratio, 0.41 [95% CI, 0.30-0.56]) and
the progression-free rate from 20% to 15% (OR, 0.74 [95% CI, 0.45-1.22])
compared with various intravesical chemotherapy agents.49 Rates of adverse effects are
common (up to 60% in some series) and can manifest as chemical cystitis,
irritative voiding symptoms, and malaise.50 In a small fraction of patients
(1%), systemic absorption of BCG may lead to severe sepsis and require
treatment with antibiotics, steroids, and cessation of BCG therapy.
BCG Shortage, Failure, and Alternative Therapies
Despite
its preferred status, BCG has become difficult to obtain in the US due to
supply chain interruptions.51 Regulatory hurdles, financial
disincentives for pharmaceutical companies, and manufacturing challenges all
contribute to decreased production amidst an increasing demand for BCG.52 In patients for whom urologists
are unable to obtain BCG or for patients with BCG therapy failure, few
alternatives exist. For any patient with BCG failure, radical cystectomy should
be considered. One FDA-approved option for patients with CIS after BCG therapy
is valrubicin; however, only 20% of patients are tumor-free at 12 months and
less than 10% remain so beyond 12 months.53
Sequential
gemcitabine-docetaxel is also used by some clinicians. In a retrospective
cohort study of 276 patients with recurrent NMIBC, prior BCG therapy, and
median follow-up of 22.9 months, this combination provided durable
recurrence-free survival rates of 60% at 1 year and 46% at 2 years.54 Recently, the FDA approved the
systemic checkpoint inhibitor pembrolizumab, based on KEYNOTE-057, a phase 2
single-group clinical trial in patients with high-risk BCG-unresponsive NMIBC
showing a complete response rate of 41%; only 46% of complete responders (about
19%) maintained this response at 12 months.55 Given the need for additional
therapies for BCG-unresponsive disease, the FDA may consider approval for
therapeutics based on single-group studies that demonstrate approximately 30%
response at 12 months.56 Several promising intravesical
therapies, such as nadoferagene firadenovec (a nonreplicating recombinant
adenovirus carrying the IFNα2b gene), vincinium (an epithelial
cell adhesion molecule gene [EPCAM]–targeted Pseudomonas exotoxin
A), and ALT-803 (an IL-15 superagonist), have demonstrated some efficacy in
patients with BCG-unresponsive disease.51
Muscle-Invasive Bladder Cancer
Muscle-invasive
bladder cancer represents the remaining 30% of localized disease. Treatment for
patients with MIBC consists of neoadjuvant therapy followed by radical
cystectomy, pelvic lymph node dissection, and urinary diversion, or a
bladder-sparing protocol, such as chemoradiation or partial cystectomy, in
selected patients (Table 5).4 Strategies to improve adherence
and enhance tolerability of treatment are critical to improve outcomes for
patients with MIBC, as reports demonstrate that more than one-half of patients
do not receive curative-intent treatment.57
Neoadjuvant Systemic Therapy
Neoadjuvant
chemotherapy prior to radical cystectomy is recommended in both the AUA
(strong/B) and EAU (strong/1a) guidelines.4,7 In the pivotal Southwest Oncology
Group 8710 randomized trial, an absolute improvement in survival of 31 months
was demonstrated with the addition of neoadjuvant chemotherapy prior to
cystectomy.58 A meta-analysis of 15
prospective studies included more than 3000 patients who received neoadjuvant
chemotherapy prior to local therapy with surgery or radiation and showed an
overall survival benefit (HR, 0.87 [95% CI, 0.79-0.96]; P < .01).59 In a subgroup analysis of those
who received cisplatin-based therapy, the absolute improvement in overall
survival was 8% at 5 years. Current practice supports the use of accelerated or
dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin or gemcitabine
and cisplatin, and an ongoing phase 3 study (VESPER) is actively comparing
these regimens.60-62 Preliminary data from this trial
demonstrate higher complete response rates in patients receiving dose-dense
methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) vs gemcitabine + cisplatin
(42% vs 36%, P = .02). Up to 50% of patients will not be
cisplatin-eligible for 1 or more of the following reasons: Eastern Cooperative
Oncology Group performance status 2 or greater, creatinine clearance less than
60mL/min, grade 2 or greater hearing loss, grade 2 or greater neuropathy, or
New York Heart Association class III heart failure.63 Carboplatin, while tolerated
with diminished kidney function, is an unacceptable alternative to first-line
neoadjuvant chemotherapy because of poorer efficacy.64 Neoadjuvant systemic
immunotherapy with pembrolizumab has shown promise in a prospective
single-group phase 2 trial of 50 patients with MIBC, with 42% of patients
achieving pathologic complete response and up to 54% downstaged to pT1 or lower
disease.65 Updated results in 114 patients
confirmed these findings but also demonstrated efficacy in patients with
variant histology (particularly squamous cell and lymphoepithelioma-like
carcinoma), who traditionally do not respond to neoadjuvant chemotherapy,
likely given higher tumor mutational burden and PD-L1 expression in a subset of
these patients.66 While pathologic complete
responses can be achieved, not all patients benefit from neoadjuvant treatment;
therefore, biomarkers such as molecular subtype and specific alterations in DNA
damage repair genes may guide utilization.
Radical Cystectomy, Pelvic Lymph Node Dissection, and Urinary
Diversion
Radical
cystectomy involves removal of the bladder, prostate, and seminal vesicles in
men and the uterus, fallopian tubes, ovaries, and anterior vagina in women.
Lymph node dissection is essential during curative-intent radical cystectomy
and is supported by the AUA (strong/B), the EAU (strong/3), and the NCCN. Lymph
node dissection provides important prognostic information and guides adjuvant
therapy, as up to 25% and 8% of patients with MIBC and high-risk NMIBC will
harbor lymph node metastases at the time of radical cystectomy. Lymph node
dissection may also provide a therapeutic benefit, as approximately 20% of
patients with positive lymph nodes will have long-term survival with a
meticulous dissection.67 A systematic review reported on
7 studies with more than 13 000 patients and showed an increase in the 5-year
overall survival from 25% to 50%, to 64% to 68%, with the performance of lymph
node dissection.68 However, the extent of lymph
node dissection during cystectomy remains controversial, as the first
prospective RCT found no benefit to extended lymph node dissection in patients
undergoing cystectomy in 5-year recurrence-free survival (65% vs 59%; HR, 0.84; P = .36),
cancer-specific survival (76% vs 65%; HR, 0.70; P = .10), or
overall survival (59% vs 50%; HR, 0.78; P = .12).69 The conclusions drawn by that
trial can be contested, however, because of the large number of lymph nodes
removed in both the limited and extended lymph node dissection cohorts
(obscuring comparisons between low and high lymph node removal), the exclusion
of patients receiving neoadjuvant chemotherapy, as well as the inclusion of
patients with high-grade NMIBC, who are less likely to have lymph node–positive
disease. Another active trial (SWOG 1011 [NCT01224665])
addresses this potential weakness by excluding patients at lower risk of lymph
node metastases, such as those with NMIBC. However, that trial allows for
neoadjuvant chemotherapy and a less aggressive dissection in the extended
lymphadenectomy group that may mitigate potential differences in outcomes
between groups.
Urinary
diversion at time of cystectomy may take several forms: an incontinent ileal
conduit, an orthotopic neobladder, or a continent cutaneous diversion (Figure).70 Selection of the
urinary diversion type should come from a well-informed discussion of the
risks, benefits, and postoperative expectations between the patient, the
family, and the surgeon and incorporates patient- and tumor-specific factors.
In clinical practice, more than 80% of patients undergo an ileal conduit
urinary diversion, given the frailty of the patient population, the relative
familiarity of this operation to the majority of urologists, and a potentially
reduced frequency of postoperative complications.71
Radical
cystectomy series have demonstrated 90-day complication rates in nearly
two-thirds of patients and mortality ranging from 1.5% to 2.0% at 30 days
postoperatively.72,73 In large national databases and
institutional series, readmission rates are approximately 25% within 30 days of
discharge.74 Postoperative complications are
most commonly gastrointestinal (29%), infectious (25%), wound-related (15%),
and genitourinary (11%).72 There are many long-term
sequelae of urinary diversion that should be considered in the primary
management of the care of patients who have undergone cystectomy. Absorption of
ammonium chloride and bicarbonate wasting in intestinal diversions result in
metabolic acidosis, which may require bicarbonate supplementation. Use of long
segments of ileum comes at the cost of physiologic vitamin B12 resorption,
and consequently serum vitamin B12 levels should be monitored
annually in these patients. Obstruction from ureterointestinal anastomotic
strictures and urinary retention in continent diversions can lead to
hydroureteronephrosis (pathologic dilation of the renal pelvis and ureter in
response to slow draining of the collecting system) and renal dysfunction, and
recurrent urinary tract infection.75
Bladder-Sparing Approaches
A
regimen of maximal TURBT followed by radiosensitizing chemotherapy and
radiation, dubbed “trimodal therapy” (TMT), is an alternative to cystectomy
(AUA, strong/B; EAU, strong/2b) for patients who decline or are ill suited for
surgery.4,7 Chemotherapy used in TMT is often
combination cisplatin with fluorouracil or paclitaxel, or fluorouracil with
mitomycin C, or cisplatin-alone (NCCN, preferred/2A) or low-dose gemcitabine
(NCCN, other/2B), and functions both as a radiosensitizing agent as well as
systemic treatment for any micrometastatic disease.8 In the absence of RCTs, large
population- and hospital-based registry studies suggest poorer overall survival
of TMT relative to cystectomy.76,77 However, a systematic review
demonstrated that 5-year overall survival rates of 48% to 60% can be reached
with TMT with prompt salvage cystectomy, if indicated.78 Partial cystectomy performed for
curative intent may also be appropriate for a select group of patients.79 Several studies are now
evaluating the potential synergy between radiation therapy and immunotherapy,
including SWOG/RTG 1806, a phase 3 randomized study of conventional TMT with
and without atezolizumab, a PD-L1 inhibitor (NCT03775265).
Given the morbidity and effect on quality of life associated with both radical
cystectomy and TMT, efforts are under way to tailor therapy to tumor molecular
profiles, with the goal of increasing treatment efficacy and perhaps organ
preservation, as in the RETAIN (NCT02710734)
and ALLIANCE (NCT03609216) trials.
Advanced and Metastatic Disease
Only
4% of patients with newly diagnosed bladder cancer present with metastatic
disease. Metastatic bladder cancer has a poor prognosis, with a median survival
with standard chemotherapy of approximately 13 to 15 months.80,81 For decades, the mainstay of
treatment has been cisplatin-based cytotoxic chemotherapy (Table 5). Recent advances, however, have
provided additional treatments such as immunotherapy, targeted therapy, and
antibody-drug conjugates, as second- and third-line options and as first-line
options for patients with poor performance status or renal dysfunction who are
ineligible to receive cisplatin (Table 6).8
Adjuvant Therapy
The
role of adjuvant chemotherapy in patients with adverse pathologic features such
as extravesical extension or node-positive disease after cystectomy remains
controversial because prospective data do not support its use. One phase 3
trial randomized 284 patients who underwent radical cystectomy with
pT3/pT4/node-positive disease and found no overall survival benefit in
immediate postoperative vs delayed salvage chemotherapy (median overall
survival, 6.7 vs 4.6 years; HR, 0.78 [95% CI, 0.56-1.08]; P = .13)
at median follow-up of 7 years (interquartile range, 5.2-8.7).82 In the absence of high-quality
evidence, guidelines recommend considering cisplatin-based adjuvant
chemotherapy for patients who have high-risk pathologic features and did not
receive neoadjuvant chemotherapy.64
Cytotoxic Chemotherapy
Cisplatin
is essential to maximize efficacy of cytotoxic chemotherapy regimens.
Guidelines recommend gemcitabine + cisplatin or dose-dense MVAC as first-line
treatment for patients with metastatic disease (EAU, strong/1b; NCCN,
preferred/2A). Gemcitabine + cisplatin is generally preferred, especially for
frail patients, given the improved adverse-effect profile compared with MVAC.
This was demonstrated in a phase 3 randomized trial of 405 patients showing
that those in the MVAC group had significantly higher rates of grade 3 and 4
mucositis, neutropenia, neutropenic fever, and neutropenic sepsis, despite
equivalent oncologic outcomes.81 The rationale for dose-dense
MVAC comes from a phase 2/3 study of 263 patients with locally advanced or
metastatic urothelial cancer that showed an improved objective response rate
(72% vs 58%), complete response rate (25% vs 11%), median progression-free
survival (9.5 vs 8.1 months; HR, 0.73 [95% CI, 0.56-0.95]), and overall
survival (15.1 vs 14.9 months; HR, 0.76 [95% CI, 0.58-0.99]) compared with
standard MVAC. In cisplatin-ineligible patients, carboplatin is an inferior
alternative and should not be used in cisplatin-fit patients (EAU, strong/2a).
Carboplatin-gemcitabine is an option in cisplatin-ineligible patients (NCCN,
preferred/2A) but was shown to have a relatively worse objective response rate
(0.36 [95% CI, 0.30-0.42]) and median overall survival (range, 7.2-10.0 months)
in a meta-analysis.93
Immunotherapy
The
high mutational burden of bladder cancer renders it susceptible to
immunotherapy, particularly with checkpoint inhibitors, monoclonal antibodies
against programmed cell death-1 (PD-1) and its ligand, PD-L1. Checkpoint
pathways are endogenous mechanisms regulating autoimmunity and can be exploited
by cancer cells to evade the immune response.94 Since 2016, 5 checkpoint
inhibitors have been approved for the treatment of bladder cancer at various
stages of disease. In the KEYNOTE-045 phase 3 trial, 542 patients with advanced
disease who progressed with first-line therapy were randomized to pembrolizumab
(anti-PD-1) vs second-line chemotherapy. Patients receiving pembrolizumab
experienced improved overall survival (10.3 vs 7.4 months; HR, 0.73 [95% CI,
0.59-0.91]; P = .002) at median follow-up of 14.1 months (range,
9.9–22.1). In KEYNOTE-052, a single-group phase 2 study, pembrolizumab as
first-line therapy in cisplatin-ineligible patients yielded an objective
response rate of 24%, with 5% complete responses.83,84 Despite promising phase 2 data,
atezolizumab (anti-PD-L1) did not improve overall survival (11.1 vs 10.6
months; HR, 0.87 [95% CI, 0.63-1.21]; P = .41) in a phase 3
randomized trial (IMvigor211) of patients who progressed with platin-based
therapy, when compared with second-line chemotherapy at median follow-up of
17.3 months (range, 0-24.5).85 Both drugs have been approved as
second-line agents or as first-line agents for cisplatin-ineligible patients
whose tumors reach threshold PD-L1 expression on immunohistologic staining.
Avelumab and durvalumab (anti-PD-L1), and nivolumab (anti-PD-1) are also
approved as second-line agents demonstrating clinical benefit in the advanced
or metastatic setting.86-88 With the approval of newer
agents, efforts to identify rational combinations and delineate sequence of
treatment are under way.
Targeted Therapies and Antibody-Drug Conjugates
Fibroblast
growth factor receptor (FGFR) is a receptor tyrosine kinase involved in cell
proliferation, survival, and migration and is a target in bladder and upper
tract urothelial cancer, particularly in luminal-subtype tumors. A recent phase
2 study (BLC2001) in 99 patients with locally advanced and metastatic disease
who did not respond to prior therapy found a 40% objective response rate with
oral erdafitinib, a pan-FGFR inhibitor, resulting in FDA approval in the
second-line setting.89 Notably, FGFR mutations are more
frequent in the upper tract (≈30%) than the bladder (≈14%), based on small
sample size sequencing studies and Cancer Genome Atlas data.95
Similarly,
antibody-drug conjugates exploit highly expressed tumor proteins as targets for
drug delivery.96 One such agent, enfortumab
vedotin, uses an anti-nectin-4 antibody linked to the microtubule-disrupting
molecule monomethyl auristatin E. A phase 2 single-group study (EV-201)
demonstrated an objective response rate of 44% among patients who progressed
following treatment with chemotherapy and immunotherapy.90 This led to FDA approval of
enfortumab vedotin in this dual-refractory setting. More recently, the FDA has
granted breakthrough designation status to combination therapy involving
enfortumab vedotin with pembrolizumab, which has shown an overall response rate
of 73%, with 16% complete responses in the first-line metastatic setting.91 Early results with sacituzumab
govitecan, an antibody-drug conjugate that links a topoisomerase inhibitor with
an antibody for trophoblast cell surface marker 2, has shown a 29% overall
response rate in a single-group phase 2 study in patients who progressed with
chemotherapy and immunotherapy.92
Limitations
This
review has several limitations. First, given the scope of the topic, a
systematic review could not be performed. Second, we also intentionally limited
our discussion to the most common forms of the disease. For example, we did not
discuss urothelial carcinoma of the upper urinary tracts, which accounts for
approximately 5% of cases. While often treated similarly, upper tract
urothelial carcinoma has unique biologic and technical considerations that
warrant consideration. Further, bladder cancer is predominantly of the pure
urothelial carcinoma histology, although variants (pure and mixed) are found in
up to 25% of patients with advanced disease. These variants, which are not
extensively discussed in this review, are driven by distinct molecular pathways
and thus carry unique management implications. Third, the treatment landscape
for bladder cancer is rapidly changing, and future therapies that may soon be
standard options could not be discussed within the scope of this review.
Conclusions
Improved
understanding of the molecular biology and genetics of bladder cancer has
evolved the way localized and advanced disease is diagnosed and treated. While
intravesical BCG has remained the mainstay of therapy for intermediate and
high-risk non–muscle-invasive bladder cancer, the therapeutic options for
muscle-invasive and advanced disease has expanded to include immunotherapy with
checkpoint inhibition, targeted therapies, and antibody-drug conjugates.
Section Editors: Edward Livingston, MD, Deputy Editor, and Mary McGrae
McDermott, MD, Deputy Editor.
Submissions: We
encourage authors to submit papers for consideration as a Review. Please
contact Edward Livingston, MD, at Edward.livingston@jamanetwork.org or Mary
McGrae McDermott, MD, at mdm608@northwestern.edu.
Corresponding Author: Karim Chamie, MD, MSHS, Institute of Urologic Oncology,
Department of Urology, David Geffen School of Medicine at UCLA, 300 Stein
Plaza, Ste 370, Los Angeles, CA 90095 (kchamie@mednet.ucla.edu).
Accepted for Publication: August 26, 2020.
Author Contributions: Drs Lenis and Chamie had full access to all of the data in
the study and take responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design, acquisition, analysis, or interpretation of
data, drafting of the manuscript, critical revision of the manuscript for
important intellectual content, and supervision: All authors.
Conflict of Interest Disclosures: Dr Chamie reported serving as a
consultant for UroGen Pharma and receiving research funding from Salix Pharma.
No other disclosures were reported.
1.Richters A, Aben KKH, Kiemeney LALM. The global burden of urinary bladder cancer: an update. World J Urol. 2020;38(8):1895-1904.PubMedGoogle ScholarCrossref
2.Siegel RL, Miller KD, Jemal is A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34.PubMedGoogle ScholarCrossref
3.Chang SS, Boorjian SA, Chou R, et al. Diagnosis and treatment
of non-muscle invasive bladder cancer: AUA/SUO guideline. J Urol. 2016;196(4):1021-1029. doi:10.1016/j.juro.2016.06.049PubMedGoogle ScholarCrossref
4.Chang SS, Bochner BH, Chou R, et al. Treatment of
non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO guideline. J Urol. 2017;198(3):552-559. doi:10.1016/j.juro.2017.04.086PubMedGoogle ScholarCrossref
5.Barocas DA, Boorjian SA, Alvarez R, et al. Microhematuria: AUA/SUFU guideline. American
Urological Association. Published 2020. Accessed June 28, 2020. https://www.auanet.org/guidelines/microhematuria
6.Babjuk M, Burger M, Comperat E, et al.
European Association of Urology non-muscle invasive bladder cancer guidelines.
Published 2020. Accessed June 21, 2020. https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/
7.Witjes JA, Bruins HM, Cathomas R, et al. European Association of Urology muscle-invasive
and metastatic bladder cancer guidelines. Published 2020. Accessed June 21, 2020. https://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-metastatic/
8.xPharm, The Comprehensive Pharmacology
Reference: bladder cancer. Science Direct. Accessed October 15, 2020. https://www.sciencedirect.com/science/article/pii/B9780080552323608189?via%3Dihub
9.Oxford Centre for Evidence-based Medicine:
levels of evidence. Updated March 2009. Accessed June 28, 2020. https://www.cebm.net/2009/06/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/
10.Cumberbatch MGK, Jubber I, Black PC, et al. Epidemiology
of bladder cancer: a systematic review and contemporary update of risk factors
in 2018. Eur Urol.
2018;74(6):784-795.PubMedGoogle ScholarCrossref
11.Shariat SF, Sfakianos JP, Droller MJ, et al. The effect of age and gender on bladder
cancer: a critical review of the literature. BJU Int. 2010;105(3):300-308. doi:10.1111/j.1464-410X.2009.09076.xPubMedGoogle ScholarCrossref
12.Shariat SF, Milowsky M, Droller MJ. Bladder cancer in the elderly. Urol Oncol. 2009;27(6):653-667. doi:10.1016/j.urolonc.2009.07.020PubMedGoogle ScholarCrossref
13.Wang Y, Chang Q, Li Y. Racial differences in urinary bladder
cancer in the United States. Sci Rep.
2018;8(1):12521. doi:10.1038/s41598-018-29987-2PubMedGoogle ScholarCrossref
14.Gild P, Wankowicz SA, Sood A, et al. Racial disparity in
quality of care and overall survival among black vs. white patients with
muscle-invasive bladder cancer treated with radical cystectomy. Urol Oncol. 2018;36(10):469.e1-469.e11. doi:10.1016/j.urolonc.2018.07.012PubMedGoogle ScholarCrossref
15.Dobruch J, Daneshmand S, Fisch M, et al. Gender and bladder cancer: a collaborative
review of etiology, biology, and outcomes. Eur
Urol. 2016;69(2):300-310.PubMedGoogle ScholarCrossref
16.Hurst CD, Alder O, Platt FM, et al. Genomic
subtypes of non-invasive bladder cancer with distinct metabolic profile and
female gender bias in KDM6A mutation frequency. Cancer Cell. 2017;32(5):701-715. doi:10.1016/j.ccell.2017.08.005PubMedGoogle ScholarCrossref
17.Freedman ND, Silverman DT, Hollenbeck AR, et al. Association between smoking and risk of
bladder cancer among men and women. JAMA.
2011;306(7):737-745. doi:10.1001/jama.2011.1142
ArticlePubMedGoogle ScholarCrossref
18.Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860-867. doi:10.1038/nature01322PubMedGoogle ScholarCrossref
19.Ishida K, Hsieh MH. Understanding urogenital
schistosomiasis-related bladder cancer: an update. Front Med (Lausanne). 2018;5(Aug):223. doi:10.3389/fmed.2018.00223PubMedGoogle ScholarCrossref
20.Wallis CJD, Mahar AL, Choo R, et al. Second
malignancies after radiotherapy for prostate cancer: systematic review and
meta-analysis. BMJ. 2016;352:i851. doi:10.1136/bmj.i851PubMedGoogle ScholarCrossref
21.Moschini M, Zaffuto E, Karakiewicz PI, et al. External beam radiotherapy increases the
risk of bladder cancer when compared with radical prostatectomy in patients
affected by prostate cancer. Eur
Urol. 2019;75(2):319-328.PubMedGoogle ScholarCrossref
22.Abern MR, Dude AM, Tsivian M, Coogan CL. The characteristics of bladder cancer
after radiotherapy for prostate cancer. Urol
Oncol. 2013;31(8):1628-1634. doi:10.1016/j.urolonc.2012.04.006PubMedGoogle ScholarCrossref
23.Knight A, Askling J, Granath F, et al. Urinary bladder cancer in Wegener’s
granulomatosis: risks and relation to cyclophosphamide. Ann Rheum Dis. 2004;63(10):1307-1311. doi:10.1136/ard.2003.019125PubMedGoogle ScholarCrossref
24.Warschkow R, Güller U, Cerny T, et al. Secondary
malignancies after rectal cancer resection with and without radiation therapy:
a propensity-adjusted, population-based SEER analysis. Radiother Oncol. 2017;123(1):139-146. doi:10.1016/j.radonc.2017.02.007PubMedGoogle ScholarCrossref
25.Chaturvedi AK, Engels EA, Gilbert ES, et al. Second cancers among 104,760 survivors of
cervical cancer: evaluation of long-term risk. J Natl Cancer Inst. 2007;99(21):1634-1643.
doi:10.1093/jnci/djm201PubMedGoogle ScholarCrossref
26.Mucci LA, Hjelmborg JB, Harris JR, et al. Familial risk and heritability of cancer
among twins in Nordic countries. JAMA.
2016;315(1):68-76. doi:10.1001/jama.2015.17703
ArticlePubMedGoogle ScholarCrossref
27.Carlo MI, Ravichandran V, Srinavasan P, et al. Cancer susceptibility mutations in patients
with urothelial malignancies. J Clin
Oncol. 2020;38(5):406-414. doi:10.1200/JCO.19.01395PubMedGoogle ScholarCrossref
28.Lim A, Rao P, Matin SF. Lynch syndrome and urologic
malignancies: a contemporary review. Curr
Opin Urol. 2019;29(4):357-363.PubMedGoogle ScholarCrossref
29.Huang D, Matin SF, Lawrentschuk N, Roupret M. Systematic review: an update on the spectrum of
urological malignancies in Lynch syndrome. Bladder
Cancer. 2018;4(3):261-268. doi:10.3233/BLC-180180PubMedGoogle ScholarCrossref
30.Lobo N, Shariat SF, Guo CC, et al. What is the significance
of variant histology in urothelial carcinoma? Eur Urol Focus. 2020;6(4):653-663.PubMedGoogle ScholarCrossref
31.Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human
cancer [published correction appears in Nature. 2013;502
(7470):258]. Nature. 2013;500(7463):415-421. doi:10.1038/nature12477PubMedGoogle ScholarCrossref
32.Matulay JT, Kamat AM. Advances in risk stratification of
bladder cancer to guide personalized medicine. F1000Res. 2018;7(0):1-13. doi:10.12688/f1000research.14903.1PubMedGoogle Scholar
33.Edwards TJ, Dickinson AJ, Natale S, et al. A prospective analysis of the diagnostic
yield resulting from the attendance of 4020 patients at a protocol-driven
haematuria clinic. BJU Int.
2006;97(2):301-305. doi:10.1111/j.1464-410X.2006.05976.xPubMedGoogle ScholarCrossref
34.Xiong Y, Li J, Ma S, et al. A meta-analysis of narrow
band imaging for the diagnosis and therapeutic outcome of non-muscle invasive
bladder cancer. PLoS One.
2017;12(2):e0170819.PubMedGoogle Scholar
35.Burger M, Grossman HB, Droller M, 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;64(5):846-854. doi:10.1016/j.eururo.2013.03.059PubMedGoogle ScholarCrossref
36.Cumberbatch MGK, Foerster B, Catto JWF, et al. Repeat transurethral resection in
non-muscle-invasive bladder cancer: a systematic review. Eur Urol. 2018;73(6):925-933.PubMedGoogle ScholarCrossref
37.Chamie K, Ballon-Landa E, Bassett JC, et al. Quality of diagnostic staging in patients
with bladder cancer: a process-outcomes link. Cancer. 2015;121(3):379-385. doi:10.1002/cncr.29071PubMedGoogle ScholarCrossref
38.Luo C, Huang B, Wu Y, Chen J, Chen L. Use of Vesical Imaging-Reporting and Data System
(VI-RADS) for detecting the muscle invasion of bladder cancer: a diagnostic
meta-analysis. Eur Radiol.
2020;30(8):4606-4614.PubMedGoogle ScholarCrossref
39.Faiena I, Rosser CJ, Chamie K, Furuya H. Diagnostic biomarkers in non-muscle invasive bladder
cancer. World J Urol.
2019;37(10):2009-2016. doi:10.1007/s00345-018-2567-1PubMedGoogle ScholarCrossref
40.Zhang Z, Fan W, Deng Q, et al. The prognostic and
diagnostic value of circulating tumor cells in bladder cancer and upper tract
urothelial carcinoma: a meta-analysis of 30 published studies. Oncotarget. 2017;8(35):59527-59538. doi:10.18632/oncotarget.18521PubMedGoogle ScholarCrossref
41.Christensen E, Birkenkamp-Demtröder K, Sethi H, et al. Early detection of metastatic relapse and
monitoring of therapeutic efficacy by ultra-deep sequencing of plasma cell-free
DNA in patients with urothelial bladder carcinoma. J Clin Oncol. 2019;37(18):1547-1557. doi:10.1200/JCO.18.02052PubMedGoogle ScholarCrossref
42.Kirkali Z, Chan T, Manoharan M, et al. Bladder cancer: epidemiology, staging and
grading, and diagnosis. Urology. 2005;66(6)(suppl
1):4-34.PubMedGoogle ScholarCrossref
43.Ritch CR, Velasquez MC, Kwon D, et al. Use and validation of the AUA/SUO risk
grouping for nonmuscle invasive bladder cancer in a contemporary cohort. J Urol. 2020;203(3):505-511.PubMedGoogle ScholarCrossref
44.van den Bosch S, Alfred Witjes J. Long-term
cancer-specific survival in patients with high-risk, non-muscle-invasive
bladder cancer and tumour progression: a systematic review. Eur Urol. 2011;60(3):493-500. doi:10.1016/j.eururo.2011.05.045PubMedGoogle ScholarCrossref
45.Sylvester RJ, Oosterlinck W, Van Der Meijden
APM. A single immediate postoperative
instillation of chemotherapy decreases the risk of recurrence in patients with
stage Ta T1 bladder cancer: a meta-analysis of published results of randomized
clinical trials. J Urol. 2004;171(6 pt 1):2186-2190.PubMedGoogle ScholarCrossref
46.Doherty AP, Trendell-Smith N, Stirling R, et al. Perivesical fat necrosis after adjuvant
intravesical chemotherapy. BJU Int.
1999;83(4):420-423. doi:10.1046/j.1464-410x.1999.00951.xPubMedGoogle ScholarCrossref
47. Messing EM, Tangen CM, Lerner SP, et al. Effect of intravesical instillation of
gemcitabine vs saline immediately following resection of suspected low-grade
non-muscle-invasive bladder cancer on tumor recurrence: SWOG S0337 randomized
clinical trial. JAMA.
2018;319(18):1880-1888. doi:10.1001/jama.2018.4657
ArticlePubMedGoogle ScholarCrossref
48.Pettenati C, Ingersoll MA. Mechanisms of
BCG immunotherapy and its outlook for bladder cancer. Nat Rev Urol. 2018;15(10):615-625. doi:10.1038/s41585-018-0055-4PubMedGoogle ScholarCrossref
49.Sylvester RJ, van der Meijden APM, Witjes JA, Kurth K. Bacillus Calmette-Guerin versus
chemotherapy for the intravesical treatment of patients with carcinoma in situ
of the bladder: a meta-analysis of the published results of randomized clinical
trials. J Urol. 2005;174(1):86-91.PubMedGoogle ScholarCrossref
50.Brausi M, Oddens J, Sylvester R, et al. Side effects of bacillus Calmette-Guérin
(BCG) in the treatment of intermediate- and high-risk Ta, T1 papillary
carcinoma of the bladder: results of the EORTC genito-urinary cancers group
randomised phase 3 study comparing one-third dose with full dose and 1 year
with 3 years of maintenance BCG. Eur
Urol. 2014;65(1):69-76.PubMedGoogle ScholarCrossref
51.Golla V, Lenis AT, Faiena I, Chamie K. Intravesical
therapy for non-muscle invasive bladder cancer—current and future options in
the age of bacillus Calmette-Guerin shortage. Rev Urol. 2019;21(4):145-153.PubMedGoogle Scholar
52.Bandari J, Maganty A, MacLeod LC, Davies BJ. Manufacturing and the market:
rationalizing the shortage of bacillus Calmette-Guérin. Eur Urol Focus. 2018;4(4):481-484. doi:10.1016/j.euf.2018.06.018PubMedGoogle ScholarCrossref
53.Steinberg G, Bahnson R, Brosman S, et al. Efficacy and safety of valrubicin for the
treatment of bacillus Calmette-Guerin refractory carcinoma in situ of the
bladder. J Urol.
2000;163(3):761-767. doi:10.1016/S0022-5347(05)67799-3PubMedGoogle ScholarCrossref
54.Steinberg RL, Thomas LJ, Brooks N, et al. Multi-institution
evaluation of sequential gemcitabine and docetaxel as rescue therapy for
nonmuscle invasive bladder cancer. J Urol. 2020;203(5):902-909. doi:10.1097/ju.0000000000000688PubMedGoogle ScholarCrossref
55.Balar AV, Kulkarni GS, Uchio EM, et al. Keynote 057: phase II trial of
pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle
invasive bladder cancer (NMIBC) unresponsive to bacillus Calmette-Guérin
(BCG). J Clin Oncol. 2019;37(7
suppl):350. doi:10.1200/JCO.2019.37.7_suppl.350Google ScholarCrossref
56.Lerner SP, Bajorin DF, Dinney CP, et al. Summary and recommendations from the
National Cancer Institute’s Clinical Trials Planning Meeting on Novel
Therapeutics for Non-Muscle Invasive Bladder Cancer. Bladder Cancer. 2016;2(2):165-202.PubMedGoogle ScholarCrossref
57.Westergren DO, Gårdmark T, Lindhagen L, Chau A, Malmström PUA. A nationwide, population based analysis of patients with
organ confined, muscle invasive bladder cancer not receiving curative intent
therapy in Sweden from 1997 to 2014. J Urol.
2019;202(5):905-912.PubMedGoogle ScholarCrossref
58.Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy
compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859-866. doi:10.1056/NEJMoa022148PubMedGoogle ScholarCrossref
59.Yin M, Joshi M, Meijer RP, et al. Neoadjuvant chemotherapy
for muscle-invasive bladder cancer: a systematic review and two-step
meta-analysis. Oncologist.
2016;21(6):708-715. doi:10.1634/theoncologist.2015-0440PubMedGoogle ScholarCrossref
60.Dash A, Pettus J, Herr H, et al. A role for neoadjuvant
gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the
bladder: a retrospective experience. Cancer. 2008;113(9):2471-2477. doi:10.1002/cncr.23848PubMedGoogle ScholarCrossref
61.von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus
methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic
bladder cancer: results of a large, randomized, multinational, multicenter,
phase III study. J Clin Oncol.
2000;18(17):3068-3077.PubMedGoogle ScholarCrossref
62.Zargar H, Espiritu PN, Fairey AS, et al. Multicenter assessment of neoadjuvant
chemotherapy for muscle-invasive bladder cancer. Eur Urol. 2015;67(2):241-249. doi:10.1016/j.eururo.2014.09.007PubMedGoogle ScholarCrossref
63.Galsky MD, Hahn NM, Rosenberg J, et al. Treatment of patients with metastatic
urothelial cancer “unfit” for cisplatin-based chemotherapy. J Clin Oncol. 2011;29(17):2432-2438. doi:10.1200/JCO.2011.34.8433PubMedGoogle ScholarCrossref
64.Chang SS, Bochner BH, Chou R, et al. Treatment of non-metastatic muscle-invasive
bladder cancer: AUA/ASCO/ASTRO/SUO guideline. J Urol. 2017;198(3):552-559.
doi:10.1016/j.juro.2017.04.086PubMedGoogle ScholarCrossref
65.Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as neoadjuvant therapy before
radical cystectomy in patients with muscle-invasive urothelial bladder
carcinoma (PURE-01): an open-label, single-arm, phase II study. J Clin Oncol. 2018;36(34):3353-3360. doi:10.1200/JCO.18.01148PubMedGoogle ScholarCrossref
66.Necchi A, Raggi D, Gallina A, et al. Updated results of PURE-01 with preliminary
activity of neoadjuvant pembrolizumab in patients with muscle-invasive bladder
carcinoma with variant histologies. Eur
Urol. 2020;77(4):439-446. doi:10.1016/j.eururo.2019.10.026PubMedGoogle ScholarCrossref
67.Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of
invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol. 2001;19(3):666-675. doi:10.1200/JCO.2001.19.3.666PubMedGoogle ScholarCrossref
68.Bruins HM, Hernandez V, Veskimae E, et al. Does the extent of lymphadenectomy impact
survival after radical cystectomy: a systematic review. Eur Urol Suppl.
2014;13(1):e118-e118b. doi:10.1016/S1569-9056(14)60119-6Google ScholarCrossref
69.Gschwend JE, Heck MM, Lehmann J, et al. Extended versus limited lymph node
dissection in bladder cancer patients undergoing radical cystectomy: survival
results from a prospective, randomized trial. Eur Urol. 2019;75(4):604-611. doi:10.1016/j.eururo.2018.09.047PubMedGoogle ScholarCrossref
70.Nieuwenhuijzen JA, de Vries RR, Bex A, et al. Urinary diversions after cystectomy: the
association of clinical factors, complications and functional results of four
different diversions. Eur Urol.
2008;53(4):834-842. doi:10.1016/j.eururo.2007.09.008PubMedGoogle ScholarCrossref
71.Bachour K, Faiena I, Salmasi A, et al. Trends in urinary diversion after radical
cystectomy for urothelial carcinoma. World J
Urol. 2018;36(3):409-416. doi:10.1007/s00345-017-2169-3PubMedGoogle ScholarCrossref
72.Shabsigh A, Korets R, Vora KC, et al.
Defining early morbidity of radical cystectomy for patients with bladder
cancer using a standardized reporting methodology. Eur Urol. 2009;55(1):164-174. doi:10.1016/j.eururo.2008.07.031PubMedGoogle ScholarCrossref
73.Quek ML, Stein JP, Daneshmand S, et al. A
critical analysis of perioperative mortality from radical cystectomy. J Urol. 2006;175(3, pt 1):886-889. doi:10.1016/S0022-5347(05)00421-0PubMedGoogle ScholarCrossref
74.Hu M, Jacobs BL, Montgomery JS, et al. Sharpening
the focus on causes and timing of readmission after radical cystectomy for
bladder cancer. Cancer.
2014;120(9):1409-1416. doi:10.1002/cncr.28586PubMedGoogle ScholarCrossref
75.Gerharz EW, Turner WH, Kälble T, Woodhouse CRJ. Metabolic and functional consequences of urinary
reconstruction with bowel. BJU Int.
2003;91(2):143-149. doi:10.1046/j.1464-410X.2003.04000.xPubMedGoogle ScholarCrossref
76.Williams SB, Shan Y, Jazzar U, et al. Comparing
survival outcomes and costs associated with radical cystectomy and trimodal
therapy for older adults with muscle-invasive bladder cancer. JAMA Surg. 2018;153(10):881-889. doi:10.1001/jamasurg.2018.1680
ArticlePubMedGoogle ScholarCrossref
77.Cahn DB, Handorf EA, Ghiraldi EM, et al. Contemporary
use trends and survival outcomes in patients undergoing radical cystectomy or
bladder-preservation therapy for muscle-invasive bladder cancer. Cancer. 2017;123(22):4337-4345. doi:10.1002/cncr.30900PubMedGoogle ScholarCrossref
78.Ploussard G, Daneshmand S, Efstathiou JA, et al. Critical analysis of bladder sparing with
trimodal therapy in muscle-invasive bladder cancer: a systematic review. Eur Urol. 2014;66(1):120-137.PubMedGoogle ScholarCrossref
79.Knoedler JJ, Boorjian SA, Kim SP, et al. Does partial cystectomy compromise
oncologic outcomes for patients with bladder cancer compared to radical
cystectomy? a matched case-control analysis. J Urol. 2012;188(4):1115-1119. doi:10.1016/j.juro.2012.06.029PubMedGoogle ScholarCrossref
80.Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of an EORTC phase III
trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC
in advanced urothelial tract tumours. Eur J
Cancer. 2006;42(1):50-54. doi:10.1016/j.ejca.2005.08.032PubMedGoogle ScholarCrossref
81.von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus
methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic
bladder cancer: results of a large, randomized, multinational, multicenter,
phase III study. J Clin Oncol. 2000;18(17):3068-3077.
doi:10.1200/JCO.2000.18.17.3068PubMedGoogle ScholarCrossref
82.Sternberg CN, Skoneczna I, Kerst JM, et al. Immediate versus deferred chemotherapy
after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma
of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3
trial. Lancet Oncol.
2015;16(1):76-86. doi:10.1016/S1470-2045(14)71160-XPubMedGoogle ScholarCrossref
83.Bellmunt J, de Wit R, Vaughn DJ, et al; KEYNOTE-045 Investigators. Pembrolizumab as
second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015-1026. doi:10.1056/NEJMoa1613683PubMedGoogle ScholarCrossref
84.Balar AV, Castellano D, O’Donnell PH, et al. First-line pembrolizumab in
cisplatin-ineligible patients with locally advanced and unresectable or
metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2
study. Lancet Oncol. 2017;18(11):1483-1492.
doi:10.1016/S1470-2045(17)30616-2PubMedGoogle ScholarCrossref
85.Powles T, Durán I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in
patients with platinum-treated locally advanced or metastatic urothelial
carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised
controlled trial. Lancet.
2018;391(10122):748-757. doi:10.1016/S0140-6736(17)33297-XPubMedGoogle ScholarCrossref
86.Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial
carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm,
phase 2 trial. Lancet Oncol.
2017;18(3):312-322. doi:10.1016/S1470-2045(17)30065-7PubMedGoogle ScholarCrossref
87.Powles T, O’Donnell PH, Massard C, et al. Efficacy and safety of durvalumab in
locally advanced or metastatic urothelial carcinoma: updated results from a
phase 1/2 open-label study. JAMA
Oncol. 2017;3(9):e172411. doi:10.1001/jamaoncol.2017.2411
ArticlePubMedGoogle Scholar
88.Apolo AB, Infante JR, Balmanoukian A, et al. Avelumab, an anti-programmed death-ligand 1
antibody, in patients with refractory metastatic urothelial carcinoma: results
from a multicenter, phase Ib study. J Clin
Oncol. 2017;35(19):2117-2124. doi:10.1200/JCO.2016.71.6795PubMedGoogle ScholarCrossref
89.Loriot Y, Necchi A, Park SH, et al; BLC2001
Study Group. Erdafitinib in locally advanced or metastatic urothelial
carcinoma. N Engl J Med.
2019;381(4):338-348. doi:10.1056/NEJMoa1817323PubMedGoogle ScholarCrossref
90.Rosenberg JE, O’Donnell PH, Balar AV, et al. Pivotal trial of enfortumab vedotin in
urothelial carcinoma after platinum and anti-programmed death 1/programmed
death ligand 1 therapy. J Clin Oncol.
2019;37(29):2592-2600.PubMedGoogle ScholarCrossref
91.Rosenberg JE, Flaig TW, Friedlander TW, et al. Study EV-103: preliminary durability
results of enfortumab vedotin plus pembrolizumab for locally advanced or
metastatic urothelial carcinoma. J Clin
Oncol. 2020;38(6 suppl):441. doi:10.1200/jco.2020.38.6_suppl.441Google ScholarCrossref
92.Tagawa ST, Balar A, Petrylak DP, et al. Initial results from TROPHY-U-01: a phase
II open-label study of sacituzumab govitecan in patients (Pts) with metastatic
urothelial cancer (mUC) after failure of platinum-based regimens (PLT) or
immunotherapy. Ann Oncol. 2019;30(suppl
5):v890-v891. doi:10.1093/annonc/mdz394.049Google ScholarCrossref
93.Freshwater T, Li H, Valiathan C, et al. Systematic literature review and
meta-analysis of response to first-line therapies for advanced/metastatic
urothelial cancer patients who are cisplatin ineligible. Am J Clin Oncol. 2019;42(10):802-809. doi:10.1097/COC.0000000000000585PubMedGoogle ScholarCrossref
94.Donin NM, Lenis AT, Holden S, et al. Immunotherapy
for the treatment of urothelial carcinoma. J Urol.
2017;197(1):14-22. doi:10.1016/j.juro.2016.02.3005PubMedGoogle ScholarCrossref
95.Robinson BD, Vlachostergios PJ, Bhinder B, et al. Upper tract urothelial carcinoma has a
luminal-papillary T-cell depleted contexture and activated FGFR3 signaling. Nat Commun. 2019;10(1):2977. doi:10.1038/s41467-019-10873-yPubMedGoogle ScholarCrossref
96.Sarfaty M, Rosenberg JE. Antibody-drug
conjugates in urothelial carcinomas. Curr
Oncol Rep. 2020;22(2):13. doi:10.1007/s11912-020-0879-yPubMedGoogle ScholarCrossref
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