136  Management Strategies for Non–Muscle-Invasive
Bladder Cancer (Ta, T1, and CIS)
Joseph Zabell, MD, and Badrinath R. Konety, MD, MBAa
N
on–muscle-invasive bladder cancer (NMIBC) is the term
commonly applied to malignant urothelial tumors that have
not invaded the detrusor muscle of the bladder (Epstein
et al., 1998; Smith et al., 1999). This terminology encompasses the
relatively benign course of low-grade papillary tumors, the more
aggressive clinical course of high-grade tumors including urothelial
carcinoma in situ (CIS), and high-grade Ta and T1 tumors. Approxi-
mately 70% to 80% of bladder tumors are non–muscle invasive
at presentation with 60% to 70% as stage Ta, 20% to 30% as T1,
and approximately 10% as CIS (Fig. 136.1) (Aldousari and Kassouf,
2010; Ro et al., 1992).
Painless hematuria (either visible or non-visible) is the most
common presenting symptom of NMIBC. Patients with visible
hematuria have reported rates of bladder cancer much higher
than that observed in patients with non-visible (>3 RBC/hpf on
microscopic urinalysis) hematuria (Tan et al., 2018). A recent
prospective study of more than 3500 patients from 40 institutions
found that 10.9% of patients with visible hematuria had bladder
cancer, whereas non-visible hematuria was associated with bladder
cancer in 2.5% (Tan et al., 2018). Other studies have found a
prevalence of bladder cancer in 0.3% to 4.7% of patients with
non-visible or microscopic hematuria (Kang et al., 2015; Khadra
et al., 2000). Bladder cancer patients younger than 40 years are more
likely to have visible hematuria rather than non-visible hematuria.
The degree of hematuria, whether visible or non-visible is not
predictive of stage and grade of cancer (Tan et al., 2018). The presence
of irritative voiding symptoms in the absence of a urinary tract
infection is also associated with CIS with some studies report-
ing rates of up to 80% (Zincke et al., 1985). In a review of 600
patients diagnosed with interstitial cystitis, 1% of the patients had
a missed diagnosis of urothelial carcinoma, although the majority
of these patients did not have hematuria (Tissot et al., 2004). Thus
cystoscopy and upper tract imaging are indicated in patients with
hematuria and/or unexplained irritative symptoms (Davis et al.,
2012; Grossfeld et al., 2001).
Recurrence is common in all patients with NMIBC but can often be
managed with multimodal treatment, including transurethral surgery
with or without intravesical immunotherapy and chemotherapy
therapy. Risk of recurrence is typically approximately 40% to 60%
but can be influenced by multiple clinical factors. Risk of progres-
sion, however, is of key concern in patients with NMIBC given the
heterogeneity of tumors in this category with rates of progression
as low as 6% in patients with low-grade Ta lesions (Leblanc et al.,
1999) to as high as 17% in high-grade T1 tumors (Palou et al., 2012).
The frequency of progression and death is shown in Table 136.1.
Considerable work has been completed in an effort to develop
clinical tools for risk stratification of patients with NMIBC. One
previously published stratification system has been developed by
the European Organization for Research and Treatment of Cancer
(EORTC) with the goal of predicting probability of recurrence and
progression at 1 and 5 years after treatment. Factors associated
with recurrence include previous recurrence, number of tumors,
and tumor size. For progression, significant factors for prognosis
a
Portions of this chapter are based on or carried forward from previous
versions of this text, as authored by J. Stephen Jones, MD, MBA, FACS.
were T stage, presence of CIS, and grade (Sylvester et al., 2006).
A similar model was developed by the Spanish Urological Club
for Oncological Treatment/Club Urologico Espanol de Tratamiento
Oncologico (CUETO) (Fernandez-Gomez et al., 2009). The EORTC
model was limited by minimal use of bacille Calmette-Guérin (BCG)
maintenance, perioperative mitomycin C (MMC), and restaging
transurethral resection of bladder tumor (TURBT) in the patient
cohorts used for model development. As a consequence, they tended
to overestimate the rate of recurrence and progression. Using data
from more recent trials incorporating patients who have received
BCG maintenance therapy, the EORTC risk assessment tool has been
updated (Cambier et al., 2016). However, the cohort is deficient
in patients with CIS and requires further independent validation.
More recently, the American Urological Association and Society
of Urologic Oncology (AUA/SUO) Guideline for the Diagnosis
and Treatment of Non–Muscle-Invasive Bladder Cancer has been
published, which created a novel risk stratification schema (Table
136.2; Chang et al., 2016). Such risk stratification models allow for
more nuanced evaluation of risk of recurrence and progression in
patients with NMIBC, therefore allowing for risk-adapted treatment
and surveillance strategies.
PATHOLOGY: GRADING AND STAGING
Pathological Staging
Tumor staging for urothelial carcinoma of the bladder is outlined
by the American Joint Committee on Cancer (AJCC) criteria that
include clinical and pathological staging outlines. Clinical stage
reflects findings in TURBT as well as radiologic and physical exam
findings with bimanual exam at time of TURBT. These findings allow
the clinician to determine if lamina propria and/or muscularis propria
are present or involved in the specimen and should assess for
lymphovascular invasion (LVI), if possible. Pathological staging is
based on surgical resection of the bladder via partial or radical
cystectomy and pathological evaluation of pelvic lymph nodes.
The bladder has three main histologic layers: (1) urothelium, (2)
suburothelial connective tissue called lamina propria, and (3) detrusor
or muscularis propria (which is absent beneath the urothelium of
diverticula). TNM staging for NMIBC includes noninvasive papil-
lary tumors confined to urothelium regardless of grade (stage Ta),
tumors invading the subepithelial tissue (lamina propria) (T1), and
carcinoma in situ/tumor in situ (CIS/Tis). The TNM grading system
is illustrated in Fig. 136.1.
Tumors invading the lamina propria can exhibit focal or extensive
invasion. Several strategies have been used to sub-stratify T1 disease;
extent of invasion is thought to correlate with progression to muscle-
invasive disease (Leivo et al., 2018). One commonly used method
includes evaluation of depth of invasion relative to the muscularis
mucosae, which is a layer of discontinuous wispy bands of smooth
muscle within the lamina propria. Tumors invading deep to the
muscularis mucosae have been found to have a worse prognosis
(Roubret et al., 2013). However, because of discontinuity of this
layer and difficulty of orientation with some TURBT specimens, the
depth of lamina propria invasion cannot be adequately assessed in
all cases using this technique (Leivo et al., 2018). Recognition of
the clinical importance of substaging of T1 tumors into T1a and
3091
3092 PART XIV  Benign and Malignant Bladder Disorders

TABLE 136.1 Estimates of Disease Progression in Non–Muscle-Invasive Bladder Cancer: World Health Organization/
International Society of Urologic Pathology Consensus Classification

TUMOR TYPE RELATIVE FREQUENCY (%) PROGRESSION (%) DEATHS (%)

NONINVASIVE
Papilloma 10 0–1 0
Papillary urothelial neoplasm of low malignant potential 20 3 0–1
Papillary cancer, low grade (TaG1) 20 5–10 1–5
Papillary cancer, high grade (TaG3) 30 15–40 10–25

INVASIVE
Papillary cancer (T1G3) 20 30–50 33

CARCINOMA IN SITU
Primary 10 >50 —
Secondary 90 — —

From Donat SM: Evaluation and follow-up strategies for superficial bladder cancer. Urol Clin North Am 30:765–766, 2003.

TABLE 136.2 American Urological Association Risk

CIS
Ta Stratification for Non–Muscle-Invasive
T1 Bladder Cancer
T2
LOW RISK INTERMEDIATE RISK HIGH RISK
T3
LG solitary Recurrence within 1 HG T1
Ta ≤ 3 cm year, LG Ta
PUNLMP Solitary LG Ta > 3 cm Any recurrent, HG Ta
LG Ta, multifocal HG Ta, >3 cm (or
multifocal)
HG Ta, ≤ 3 cm Any CIS
LG T1 Any BCG failure in
HG patient
Any variant histology
Any LVI
Any HG prostatic
urethral involvement
Fig. 136.1.  Carcinoma in situ is a high-grade, flat malignancy confined to the
urothelium. Papillary tumors confined to the urothelium are Ta, whereas papillary BCG, Bacille Calmette-Guérin; CIS, carcinoma in situ; HG, high grade;
tumors invading lamina propria are T1. The T1 tumor here intertwines with the LG, low grade; LVI, lymphovascular invasion; PUNLMP, papillary urothelial
wispy fibers of the muscularis propria but by definition does not invade the neoplasm of low malignant potential.
smooth muscle fibers of the detrusor. T2 tumors invade the detrusor muscle, From Chang et al: Diagnosis and treatment of non-muscle invasive bladder
and T3 tumors are in extravesical fat as shown. CIS, Carcinoma in situ. cancer, AUA/SUO Guideline, 2016.

T1b as part of the staging system has been proposed. The most recent
AJCC Staging Manual emphasizes the importance of assessing the
extent of lamina propria invasion; however, no specific approach to
doing so is yet universally accepted (Amin et al., 2016).
Pathological Grading
Currently, the World Health Organization (WHO)/International
Society of Urologic Pathology (ISUP) grading system from 2015 is
widely accepted and commonly used (Moch et al., 2015). This system
highlights the term urothelial cancer as being preferable to the previ-
ously common terminology of transitional cell cancer, although the
former term is still occasionally used. Since the 2004 revised classifica-
tion system was published, bladder cancer grade has been differenti-
ated between low-grade tumors and high-grade tumors, rather than
the previously published three-tiered WHO/Ash-Broder system.
Currently used common classification includes hyperplasia (flat and
papillary), reactive atypia, atypia of unknown significance, urothelial
dysplasia, urothelial CIS, urothelial papilloma, papillary urothelial
neoplasm of low malignant potential, non–muscle-invasive low-grade
papillary urothelial carcinoma, and non–muscle-invasive high-grade
papillary urothelial carcinoma.
Essentially benign papillary tumors with orderly cellular arrange-
ment, minimal architectural abnormalities, and minimal nuclear
atypia are distinct from those two grades and are designated papillary
urothelial neoplasm of low malignant potential (PUNLMP), which
are largely regarded as unlikely to progress and are considered
essentially benign. However, on the basis of this low risk, the WHO
recommends that such pathology reports contain the note, “Patients
with these tumors are at risk of developing new bladder tumors
(‘recurrence’), usually of similar histology. However, occasionally
these subsequent lesions manifest as urothelial carcinoma (UC),
such that follow-up of the patient is warranted” (Epstein et al., 1998).
Papillomas are truly benign and not associated with risk of progression
(Figs. 136.2 through 136.5; also see Fig. 136.1).
Tumor Biology
Low-grade tumors and high-grade tumors have very different natural
histories, consistent with grade being among the most important
 Chapter 136  Management Strategies for Non–Muscle-Invasive Bladder Cancer (Ta, T1, and CIS)
Fig. 136.2.  The urothelium is thickened, but cells and nuclei are normal in
papillary urothelial neoplasm of low malignant potential (×40).
Fig. 136.3.  Ta low-grade tumor (×40). Cells are relatively normal but exhibit
irregularity and some nuclear differentiation.
Fig. 136.4.  Carcinoma in situ (×40) exhibits severe irregularity of cellular
structure and nuclear pleomorphism, but there is no invasion of lamina propria.
predictors of prognosis in NMIBC. Low-grade Ta lesions recur at
a rate of 50% to 70% and progress in less than 5% of cases. In
contrast, high-grade T1 lesions recur in more than 80% of cases
and progress in 50% of patients within 3 years. This behavior is
primarily grade dependent, rather than stage dependent: high-grade
3093
Fig. 136.5.  T1 (×40) high-grade tumor exhibits nesting of abnormal cells and
mitotic figures. Tumor cells can be seen invading the lamina propria in the
lower one-third of the photomicrograph.
tumors progress with similar frequency regardless of whether they
were invasive (T1) or noninvasive (Ta) (Herr, 2000b). Prognosis
also correlates with tumor size, multiplicity, papillary versus sessile
configuration, presence or absence of lymphovascular invasion,
and status of the remaining urothelium (Althausen et al., 1976;
Heney et al., 1983a, 1983b; Kunju et al., 2008; Lutzeyer et al., 1982).
The divergence in biologic behavior for low-grade versus high-grade
lesions correlates with the known dual molecular lines of genetic
development for these two pathways and supports the concept that
high-grade and low-grade cancers may essentially be considered
different diseases (Droller, 2005; Hasui et al., 1994). Chromosomal
alterations caused by oxidative DNA damage create two separate
genetic pathways to the development of UC (Cote and Chatterjee,
1999; Richter et al., 1997; Spruck et al., 1994). The first and more
common (low grade) leads to noninvasive, papillary tumors. These
usually follow an indolent course unless they convert to or are
associated with a secondary tumor of a second higher-grade pathway
(Kiemeney et al., 1993). Fibroblast growth factor receptor 3 (FGFR3)
mutations, along with chromosome 9 deletions occur in the majority
of papillomas and low-grade tumors and are related to the RAS
pathway and cell proliferation (Wolff et al., 2005).
The second pathway leads to the development of high-grade
cancer, including CIS, T1, and, ultimately, muscle-invasive carcinoma.
Such genetic alterations can be evaluated using karyotyping, micro-
satellite analysis for allelic imbalance (Mao et al., 1996), comparative
genomic hybridization (Kallioniemi et al., 1995), DNA ploidy analysis
by flow cytometry (Bittard et al., 1996), and fluorescence in situ
hybridization (FISH) (Degtyar et al., 2004). High-grade tumors tend
to have numerous and greatly variable chromosomal gains and losses.
In addition to their relatively predictable aneuploidy, high-grade
tumors can also lose all or part of chromosome 9 (Richter et al.,
1997). Although almost any chromosome can be affected, aneuploidy
of chromosomes 7, 9, and 17 is associated with especially aggressive
tumors (Degtyar et al., 2004; Olumi et al., 1990; Waldman et al.,
1991). Specific mutations have been linked to risk of progression,
including p53, p21, and pRb, which act in cooperative and synergistic
ways to promote bladder cancer progression (Chatterjee et al., 2004).
Because of these differing genetic imprints, it has been suggested
that papillary pTa tumors could almost be considered benign
and may be a completely separate disease entity in contrast to
3094 PART XIV  Benign and Malignant Bladder Disorders

high-grade tumors (Harnden, 2007; Sauter and Mihatsch, 1998). TABLE 136.3 Risk of Understaging When Cystectomy
Nevertheless, high-grade and low-grade lesions are known to coexist. Is Performed for Presumed
UC is traditionally considered a field change disease, with tumors Non–Muscle-Invasive Disease
arising at different times and sites. Rarely, patients who initially have
low-grade tumors subsequently develop high-grade tumors, often RISK (%) OF
years after the original tumors, so long-term surveillance is usually STUDY INSTITUTION UNDERSTAGING
appropriate (Holmäng and Ströck, 2012).
Stein et al., 2001 Southern California 39
Pathological Characteristics by Stage and Implications for Dutta et al., Vanderbilt University 40
Clinical Management 2001
Bianco et al., Wayne State 27
Stage Ta tumors are usually low grade. Although recurrence is 2004 University
common, especially in the setting of multiplicity, progression is Bayraktar et al., Vakif Gureba Hospital, 50
rare. However, 2.9% to 18% of Ta tumors are high grade, with an
2004 Aksaray-Istanbul,
average of 6.9% (Sylvester et al., 2005). The most important risk
factor for progression is grade, not stage (Millán-Rodríguez et al., Turkey
2000; Sylvester et al., 2005). Huguet et al., Servicio de Urologia, 27
CIS is occasionally mischaracterized as “premalignant” (Sylvester 2005 Fundació Puigvert,
et al., 2005), but it is actually a flat, noninvasive UC that is high Barcelona
grade by definition and is regarded as a precursor to the develop- Ficarra et al., University of Verona, 43
ment of invasive high-grade cancer. 2005 Italy
CIS lesions are composed of severely dysplastic urothelium.
Microscopically, tumors demonstrate disorderly histology with nuclear
atypia characteristic of high-grade malignancy; denudement of some
or all of the mucosa as a result of loss of cellular cohesion sometimes KEY POINTS: PATHOLOGY
complicates interpretation. A pathology report read as dysplasia or
• Malignant tumors are classified as low grade or high grade,
atypia can create confusion. Most pathologists consider mild examples
regardless of invasion.
of these entities to be benign. However, lesions interpreted as severe/
• High- and low-grade cancers are often considered
high-grade dysplasia are regarded as being the same entity as CIS
essentially separate diseases based on disparate genetic
(Epstein et al., 1998).
development, biologic behavior, and management
From 40% to 83% of patients with CIS develop muscle invasion
strategies.
if untreated, especially if associated with papillary tumors (Althau-
• The most important risk factor for progression is grade.
sen et al., 1976). Among patients thought to have CIS alone, up to
• CIS is a precursor as well as a risk factor for progression,
20% who are treated with cystectomy are found to actually contain
invasion, and metastasis.
invasion on final pathology (Shariat et al., 2006). The presence of
• Papillary tumors with orderly cellular arrangement,
CIS in specimens from cystectomy performed for presumed T1 tumors
minimal architectural abnormalities, and minimal nuclear
was associated with upstaging in 55% of patients in one series,
atypia are designated PUNLMP.
compared with 6% upstaging in patients without CIS (Masood et al.,
2004). In a series of 1500 patients, CIS was the second most important
prognostic factor after grade (Millán-Rodríguez et al., 2000). Mul-
ticentricity presents another ominous characteristic of CIS (Koch ENDOSCOPIC SURGICAL MANAGEMENT
and Smith, 1996). The presence of irritative voiding symptoms has Procedures
been associated with diffuse disease, invasion, and a compromised
prognosis, but there is no consensus on this finding in the literature Upon the identification of a bladder tumor during office-based
(Smith et al., 1999; Sylvester et al., 2005). The incidence of node- cystoscopy, the location, number, and morphology of tumors are
positive disease in patients with CIS only who undergo radical recorded, as is involvement of areas likely to reflect extravesical
cystectomy can be up to 3% (Shariat et al., 2006). extension such as the ureteral orifices and bladder neck or prostatic
T1 tumors are usually papillary and often have a narrow stalk; a urethra. Urinary cytology is typically obtained as a baseline and to
nodular or sessile appearance suggests deeper invasion. Deep establish the likelihood of high-grade disease. Positivity will encourage
penetration into the lamina propria, especially if involving random bladder biopsy at the time of TUR, as discussed later.
muscularis mucosae, increases the risk of recurrence and progres- Cross-sectional imaging to evaluate the upper urinary tract
sion in some reports. Lymphovascular invasion (Kim et al., 2014; such as CT urography (Fig. 136.6) is commonly performed before
Streeper et al., 2009; Tilki et al., 2013), pyuria (Azuma et al., 2013), TUR to identify other sources of hematuria and to assess the
and bladder neck involvement (Kobayashi et al., 2014) also increase extravesical urothelium given the risk of concomitant upper tract
this risk. Hydronephrosis often indicates muscle invasion. disease secondary to the “field change” nature of UC, which can
There is significant potential for understaging in patients with affect such tissue throughout the urinary tract. Retrograde pyelography
high-grade, apparently non–muscle-invasive tumors, especially those or ureteroscopy can be planned for any upper tract abnormalities
that appear to be stage T1. At time of cystectomy many tumors identified. CT urography, MR urography, or retrograde pyelography
are found to be more extensive than what was indicated by the are typically used to evaluate for upper tract lesions, with ureteroscopy
transurethral resection (TUR) specimen. Understaging errors ranging reserved for suspicious findings. Expert consensus is that patients
from 34% to 62% have been reported (Stein et al., 2001). Herr with solitary or limited low-grade Ta lesions do not need upper tract
(1999) reported considerable rates of upstaging tumors on restag- imaging except at baseline because of the very low risk of extravesical
ing TURBT of high-grade tumors, particularly T1 tumors where up disease (Chang et al., 2016; Davis et al., 2012; Goessl et al., 1997).
to 49% of tumors were found to be muscle invasive on restaging The overall risk of identifying upper tract lesions in patients with
TURBT. Studies addressing the risk of understaging of T1 tumors known history of bladder cancer is low, and upper tract tumors
are shown in Table 136.3. These data highlight the importance of occur in less than 5% of such patients. However, tumors at the
performing a more thorough second resection to accurately esti- trigone, the presence of concomitant CIS, and identification of
mate the depth of invasion and reduce the likelihood of missing high-risk disease are risk factors for the presence of upper tract disease
T1 tumors that are actually muscle invasive. This is particularly (Millán-Rodriguez et al., 2000; Palou et al., 2005).
important in patients with absence of muscle in the initial resection TURBT under regional or general anesthesia is the initial treatment
specimen. for visible lesions. This therapy is intended to be diagnostic and
 Chapter 136  Management Strategies for Non–Muscle-Invasive Bladder Cancer (Ta, T1, and CIS)
Fig. 136.6.  CT urogram demonstrating a bladder tumor along the right lateral
wall (red arrow), ultimately found to be a high-grade Ta bladder tumor.
therapeutic by providing specimens to allow for pathological deter-
mination of stage and grade, while simultaneously removing and/
or fulgurating all visible tumors. Bimanual examination of the bladder
is often performed with the patient under anesthesia before prepara-
tion and draping and is repeated after resection to allow for appropri-
ate clinical staging. Fixation or persistence of a palpable mass after
resection suggests locally advanced disease, although the additional
value of this maneuver in the era of modern imaging appears limited
and may even be misleading (Ploeg et al., 2012).
Complete visualization of the bladder should be completed using
a flexible cystoscope and/or the 30- and 70-degree rigid lens. Resection
is typically performed using continuous flow irrigation and resec-
toscope with the bladder filled only enough to visualize its contents.
This minimizes bladder wall movement and lessens thinning of
the detrusor through overdistention, thereby reducing the risk of
perforation (Koch and Smith, 1996). An outflow suction can be
used, which allows for more refined control of bladder volume and
avoids inadvertent overdistention, which could result in extravasation
through microperforations in the bladder wall. Resection is performed
piecemeal, delaying transection of tumor base or stalk until the
majority of tumor burden has been resected. Friable, low-grade
tumors can often be removed without the use of electrical energy
because the non-powered cutting loop will break off such tumors.
This minimizes the chance of bladder perforation and unnecessary
cautery damage or loss of specimens. Higher grade, more solid tumors
and the base of all tumors require the use of cutting current; cautery
yields hemostasis once the entire tumor has been resected. Lifting
the tumor edge away from detrusor lessens the chance of perfora-
tion (Holzbeierlein and Smith, 2000). There appears to be variability
in completeness of resection among surgeons as demonstrated by
previous data demonstrating variability in recurrence rates from 7.4%
to 45.8% depending on the surgeon (Brausi et al., 2002).
After all visible tumor has been resected, an additional pass
of the cutting loop or a cold-cup biopsy can be obtained to send
to pathology separately to determine the presence of muscle
invasion of the tumor base. An Ellik or similar chip evacuator can
be used to gather the chips floating in the bladder, and final confirma-
tion of hemostasis should be assessed in the presence of minimal
irrigation after all chips have been removed.
Traditionally, TUR has been performed using sterile water
because saline solutions conduct electricity and disperse energy
from the monopolar cautery cutting loop. Bipolar energy, as opposed
to monopolar energy, appears to offer some advantages. In a systematic
3095
review, Zhao et al. (2016) found that patients undergoing TUR with
bipolar energy had shorter hospital stay, less blood loss, and fewer
complications such as obturator reflex and bladder perforation. The
use of bipolar cautery allows use of saline irrigation, which can
decrease risk of TUR syndrome in cases of perforation and if the
resection is prolonged. Data suggest that tissue preservation for
pathological evaluation is at least as good as with monopolar resec-
tion, if not better. The use of general anesthesia with muscle-paralyzing
agents also prevents obturator reflex in patients with tumors along
the posterolateral bladder walls.
Resection of diverticular tumors presents significant risk of
bladder wall perforation, and accurate staging is difficult to achieve
given the absence of underlying detrusor. Invasion beyond the
diverticular lamina propria immediately involves perivesical fat (stage
T3a by definition). Resection in diverticula frequently leads to bladder
perforation. Low-grade diverticular tumors are best treated with
a combination of conservative resection and fulguration of the
base. This can be followed by subsequent repeat resection if the
final pathological interpretation is high grade. High-grade tumors
require adequate sampling of the tumor base, often including
perivesical fat, despite the near certainty of bladder perforation. In
such cases, an indwelling catheter should be left for several days to
allow for urothelial healing. Partial or radical cystectomy should
be strongly considered for high-grade diverticular lesions because
tumors can penetrate extravesically with relative ease given the
lack of a muscularis layer in the diverticula.
Anterior wall tumors and tumors at the dome in patients with
large bladders can be difficult to reach. Minimal bladder filling
combined with manual compression of the lower abdominal wall
to bring the tumor toward the resectoscope facilitates removal.
Extra-long resectoscopes available from many manufacturers are long
enough to reach the entirety of most bladders. Rarely, the creation
of a temporary perineal urethrostomy can be used to allow for better
access, particularly in the obese patient with an anterior wall or
dome tumor. Digital manipulation through the rectum or vagina
or downward compression of the suprapubic area can occasionally
facilitate resection.
Care must be taken during resection near the ureteral orifice to
prevent obstruction from scarring after fulguration. Pure cutting
current causes minimal scarring and may be safely performed,
including resection of the orifice if necessary. Resection of the
intramural ureter may lead to complete eradication of some tumors
but risks reflux of malignant cells. The clinical implications of this
are unclear (Palou et al., 1992).
As an alternative to formal TURBT, many small tumors may be
resected using the cold-cup biopsy forceps alone. This is especially
helpful in patients with thin-walled bladders, such as can be seen
in elderly females, because of risk of perforation with traditional
transurethral resection techniques. If perforation does occur in this
circumstance, the biopsy forceps typically leads to a smaller perforation
than the cutting loop, facilitating subsequent healing. A Bugbee
cauterization electrode facilitates hemostasis.
En bloc resection of bladder tumors represents another alternative,
relatively novel resection technique that can be performed with the
traditional loop electrode, Hybrid-Knife, holmium laser, Thulium laser,
or KTP laser (Kramer et al., 2015, 2017). This technique involves exci-
sion of the entire tumor with underlying segment of muscle with the
specimen being resected and extracted intact, rather than piecemeal. The
benefit of this derives from less cautery artifact, thereby allowing more
accurate assessment of muscle invasion by pathology. This technique
is most feasible in papillary tumors with a distinct stalk; however,
specimen extraction after en bloc resection may become problematic in
the case of large tumors, which may require fragmentation into pieces
to allow extraction through the resectoscope. Because of this potential
difficulty, it is thought that up to a third of tumors are not amenable
to en bloc resection given tumor size or location. Further potential
disadvantages of this technique include possible disruption of tissue
at incision line, equipment acquisition costs, and risk of excessive
tissue penetration depth (Kramer et al., 2017). Regardless, en bloc
resection provides a viable approach to intravesical management of
appropriately selected tumors. Video 136.1 demonstrates this technique.
3096 PART XIV  Benign and Malignant Bladder Disorders
If a tumor appears to be muscle invasive, biopsies of the borders
and base to establish invasion may be performed in lieu of
complete resection, given the likelihood of subsequent cystectomy.
Failure to demonstrate invasion necessitates repeat resection unless
the decision is made to proceed to cystectomy based on factors other
than muscle invasion. Using a 10-item checklist that meticulously
documents all the important elements of the TUR can enhance
adequacy of specimen that is obtained and the thoroughness of
resection (Anderson et al., 2016).
Complications of Transurethral Resection of Bladder
Tumor and Bladder Biopsy
Minor bleeding and irritative symptoms are common side effects in
the immediate postoperative period. The major complications of
uncontrolled hematuria and clinical bladder perforation occur in
1% to 6.7% of cases (Comploj et al., 2014), although up to 50%
of patients can exhibit contrast agent extravasation indicative of
minor perforation if cystography is performed (El Hayek et al., 2009).
Perforations tend to occur in elderly patients with large posterior
wall tumors, particularly in cases involving previous treatment with
multiple courses of intravesical therapy (Golan et al., 2011). The
incidence of perforation can be reduced by attention to technical
details, avoiding overdistention of the bladder, and using anesthetic
paralysis during the resection of significant lateral wall lesions to
lessen an obturator reflex response. Moreover, large, bulky tumors
and those that appear to be muscle invasive are often best resected
in a staged manner because it is believed that repeat resection can
more safely remove residual tumor if indicated.
The majority of perforations are extraperitoneal; however, intra-
peritoneal rupture is possible when tumors are resected at the dome
(Collado et al., 2000). The risk of tumor seeding from perforation
appears to be low (Balbay et al., 2005). However, anecdotal reports
have identified extravesical recurrences after perforation, theoretically
caused by seeding (Mydlo et al., 1999). It has been suggested that
the risk of tumor seeding is higher in patients who undergo surgical
repair, but this may be related to patient selection because only serious
intraperitoneal perforations are likely to be managed in this manner
(Mydlo et al., 1999; Skolarikos et al., 2005). Bladder perforation
during TUR does appears to be associated with greater risk of
recurrence and worse disease-free survival in a series published
by Comploj et al. (2014). However, neither cancer-specific nor
overall survival were affected in this series because these patients
were more likely to undergo radical cystectomy.
Extraperitoneal bladder perforation during TURBT can typically
be managed with prolonged urethral catheter drainage. Intraperi-
toneal perforation is less likely to close spontaneously and usually
requires open or laparoscopic surgical repair. Decisions for surgical
correction should be made on the basis of the extent of the perforation
and the clinical status of the patient. On occasion, a frozen section
of the resected specimen can be performed and if there is clear
evidence of muscle invasion, a cystectomy could be advised in lieu
of closure of bladder perforation. Open repair of an intraperitoneal
perforation or cystectomy will also allow for more thorough washout
of the abdomen to potentially reduce the likelihood of local seeding
from extravasated tumor.
TUR syndrome from fluid absorption is uncommon, particularly
with the use of bipolar energy, and managed in the same manner
as during transurethral resection of the prostate (TURP).
As long as resection of the ureteral orifice is performed with
pure cutting current, scarring is minimal and obstruction unlikely.
Cystoscopy to visualize efflux, which can be aided by intravenous
administration of indigo carmine or methylene blue or retrograde
ureteropyelography, can aid in determination of potential obstruction.
In tumors that are close to the ureteral orifice, placement of an
open-ended ureteral catheter before resection will help avoid encroach-
ment of the orifice during resection. If fluorescence cystoscopy is in
use as described later, the urine jet will appear green and can thus
be visualized as well. If the orifice is resected or coagulation current
is used nearby, renal ultrasonography in the postoperative period
can aid in identification of asymptomatic obstruction. In one series,
risk of ureteral stricture formation was rare at approximately 4%
after TUR of the ureteral orifice, and most cases of hydronephrosis
either resolved spontaneously or were associated with invasive disease
(Mano et al., 2012). Balloon dilation of the orifice or endoscopic
incision can relieve obstruction, but failure to respond will occasion-
ally necessitate reimplantation (Chang et al., 1989).
Repeat Transurethral Resection of Bladder Tumor
Complete tumor removal is not always possible, whether as a result
of excessive tumor volume, anatomic inaccessibility, medical instability
requiring premature cessation of initial resection, or risk of perforation.
It is important to obtain adequate muscle in the biopsy specimen
to evaluate muscle invasion, particularly in cases in which T1 disease
is identified or invasive tumor is suspected. This may also be important
for high-grade tumors, although that seems to be less critical. The
AUA and the EAU guidelines recommend obtaining muscle for
evaluation by performing a second TUR if necessary in cases of
incomplete resection, if no muscle is present in the initial specimen
and in high-grade T1 tumors, although more emphasis is placed on
this approach for T1 tumors (Babjuk et al., 2017; Chang et al., 2016).
Incomplete initial resection is often noted in such circumstances,
as evidenced by data suggesting that tumors are noted at the first
cystoscopic evaluation in up to 45% of patients (Brausi et al., 2002)
and that residual tumor is identified at the site of the initial resection
at least 40% of the time when repeat TUR is performed within
several weeks of original resection (Klan et al., 1991; Mersdorf et al.,
1998; Vogeli et al., 1998). In a review, Miladi et al. (2003) found
that a second TURBT detected residual tumor in 26% to 83% of
patients and corrected clinical staging errors in half of those patients.
In the case of high-risk, high-grade Ta tumors, multiple series
suggest that residual tumor can be identified in up to 50% of cases
(Grimm et al., 2003; Herr, 1999), and upstaging is noted in up to
15% of patients on repeat TURBT (Vianello et al., 2011). Given these
findings, AUA guidelines recommend consideration of repeat TURBT
of the primary tumor site within 6 weeks of initial TURBT in the
setting of high-risk, high-grade Ta tumors (Chang et al., 2016).
In the setting of high-grade T1 tumors, repeat TURBT is recom-
mended within 6 weeks of initial TURBT based on the well-
established risk of identifying worse prognostic findings or
upstaging to muscle-invasive disease in up to 25% to 30% of
repeat TURBT specimens (Herr, 2015; Schwaibold et al., 2000).
This is especially important if no muscle is identified on initial
pathology, where repeat resection of patients with T1 disease can
identify upstaging to muscle-invasive disease in up to 49% of
cases (Herr, 1999). Understaging is much more likely in T1 tumors
when muscle is absent compared with when muscle is present in
the specimen (64% vs. 30%) (Dutta et al., 2001). Herr (1999) reported
that a second resection changed treatment in one-third of patients.
Survival was 63% in patients who underwent a second TURBT versus
40% for those who did not in a German observational study (Grimm
et al., 2003), and recurrences appear to be lower after repeat TUR
(Sfakianos et al., 2014). Randomized data have also demonstrated
that patients with T1 disease at initial resection who undergo a
second TUR demonstrate lower rates of recurrence and progression
(Divrik et al., 2010). Furthermore, the efficacy of BCG in preventing
recurrence and progression appears to be higher in patients with
high-grade papillary tumors and CIS if a restaging TURBT was
performed before instillation of BCG (Herr, 2005). Finally, if residual
stage T1 is noted on repeat TURBT, risk of progression has been
demonstrated to be as high as 80% (Herr et al., 2007), thereby
suggesting potential benefit of early cystectomy in these patients.
Repeat resection also is helpful in the setting of a second
opinion, unless clear evidence of muscle invasion is identified
on the initial resection, especially if the outside pathology slides
are not available for review. In addition, subspecialty pathological
reinterpretation at the time of second opinion can yield information,
potentially leading to a change in management in almost one-third
of patients (Lee et al., 2010).
In summary, given the data presented earlier, patients with stage
T1 tumors merit repeat TUR. Patients with no muscle present in the
 Chapter 136  Management Strategies for Non–Muscle-Invasive Bladder Cancer (Ta, T1, and CIS)
initial specimen appear to benefit most in terms of recurrence,
progression, and cancer-specific and overall survival (Gontero et al.,
2016). As such, AUA guidelines recommend repeat TURBT of primary
tumor site, to include muscularis propria, within 6 weeks of the
initial TURBT in patients with incomplete initial resection, and
patients with stage T1 disease. These guidelines also recommend
consideration of repeat TURBT in patients with high-risk, high-
grade Ta tumors (Chang et al., 2016).
Random Bladder Biopsies
Biopsies of any suspicious areas are an important part of a complete
evaluation. Cold-cup biopsies may not provide as much information
regarding muscular invasion but provide tissue sampling without
cautery artifact (Smith, 1986; Soloway et al., 1978).
The use of random biopsies to identify CIS in otherwise normal-
appearing mucosa remains controversial. May et al. (2003) performed
random biopsies in high-risk patients and found that the results
were positive in 12.4% and altered treatment in 7%, including 14
of 1033 patients in whom the only positive tissue was in the random
biopsy specimen, rather than the primary resected tumor. However,
even when velvety red patches were sampled, only 11.9% of biopsy
specimens were positive in one report (Swinn et al., 2004). A European
Organisation for Research and Treatment of Cancer (EORTC) retro-
spective review found that 10% of random biopsy specimens were
positive (3.5% CIS) and concluded that such biopsies were not
warranted (van der Meijden et al., 1999). Fujimoto et al. (2003)
prospectively evaluated the role of random biopsies of normal-
appearing urothelium and found cancer in only 8 of 100 biopsy
samples, 5 of which were CIS. They concluded that random biopsies
are indicated only in the setting of multiple tumors or positive
cytology. The current consensus is that random biopsies are not
indicated in low-risk patients (i.e., those with low-grade papillary
tumors and negative cytology), but there remains no consensus with
regard to patients with high-grade disease, and many urologists
perform random biopsies in this setting particularly if urine cytology
is positive.
Prostatic urethral biopsy using the cutting loop may be performed,
especially if neobladder creation is anticipated for high-risk disease,
but bleeding may be more common (Holzbeierlein and Smith, 2000).
The additional value of the information obtained from cold-cup
and or loop resected urethral biopsies must be weighed against the
theoretic risk that such biopsies provide an exposed bed to aid tumor
implantation (Kiemeney et al., 1994; Yamada et al., 1996). Traditional
teaching is that TURP and TURBT of a low-grade bladder tumor
may be performed at the same setting but that resection of a
high-grade bladder tumor should not be performed coincident
to TURP to avoid tumor seeding and possible intravasation of
tumor cells likely to metastasize. Despite anecdotal reports of low-
grade tumors implanting in the prostatic urethra after simultaneous
resection, this risk appears to be small (Tsivian et al., 2003).
Laser Resection
Laser coagulation allows minimally invasive ablation of small papillary
tumors up to 2.5 cm. The neodymium : yttrium-aluminum-garnet
(Nd : YAG) laser has the best properties for use in bladder cancer.
The most significant complication of laser therapy is forward
scatter of laser energy to adjacent structures, resulting in perforation
of a hollow, viscous organ such as overlying bowel. This is rare
but more commonly occurs with the Nd : YAG laser because of its
deeper tissue penetration than with holmium (Ho):YAG and potassium
titanyl phosphate (KTP) lasers (Smith, 1986). Unless higher energy
is necessary for a very large tumor, limiting energy to 35 W precludes
exceeding 60°C on the outer bladder wall, minimizing the risk
of perforation (Hofstetter et al., 1994).
Laser therapy can be more expensive than resection because of
the cost of laser fibers, but bleeding is negligible and there is no
risk of obturator reflex. More recently en bloc resection of bladder
tumors (EBRT) has been accomplished using a Thulium laser. Tumors
from 1 to 5 cm have been resected using this technique, and it
3097
appears to be safe and comparable with standard electrical TUR with
low incidence of bleeding and bladder perforation (Kramer et al.,
2015). A systematic review of the literature has identified that en
bloc resection provides more than 95% rates of detrusor muscle in
specimen, allowing for high-quality pathological evaluation with
similar perioperative morbidity and recurrence rates to conventional
TURBT (Kramer et al., 2017).
Office-Based Endoscopic Management
Many patients with small (typically <0.5–1 cm), low-grade recurrences
can be managed safely in the office setting with use of diathermy
or laser ablation (Donat et al., 2004). Instillation of viscous or
injectable 1% to 2% lidocaine mixed with bicarbonate through a
catheter and a dwelling time of 15 to 30 minutes yields mucosal
analgesia, although pain with fulguration of 1- to 5-mm tumors is
often acceptable without analgesia. A prior tissue diagnosis and a
negative cytology for the initial tumor occurrence are mandatory to
determine whether the tumor is of high or low grade.
In addition, many small, low-grade tumors can be safely observed
until they exhibit significant growth because of the minimal risk
of progression (Pruthi et al., 2008; Soloway et al., 2003).
Enhanced Cystoscopic Techniques: Fluorescence
Cystoscopy, Narrow Band Imaging, Optical Coherent
Tomography, and Confocal Laser Endomicroscopy
Endoscopically, urologists can suspect malignancy based solely on
the presence of visible changes such as tumors or “red spots.” However,
a multicenter study found that 37% of the biopsies performed on
the basis of suspicious endoscopic findings resulted in a false-negative
biopsy, emphasizing the subjectivity and attendant false-positive
and false-negative rates of cystoscopy (Riedl et al., 2001). The
imperfect sensitivity of cystoscopy potentially explains, at least
in part, the high rate of cancer recurrence soon after complete
removal of all visible tumors. It is likely that in many such cases,
cancer was already present but not visible at the time of resection
and simply became visible at follow-up when it became morphologi-
cally abnormal enough to differentiate from adjacent normal uro-
thelium. To aid in identification of such tumors or satellite lesions,
numerous techniques have been developed to enhance the use of
standard cystoscopy.
Photoactive porphyrins accumulate preferentially in neoplastic
tissue. Under blue light they emit red fluorescence, which can
help in the diagnosis of indiscernible malignant lesions. Originally,
studies conducted using intravesical application of 5-aminolevulinic
acid (5-ALA), a precursor of photoactive porphyrin, resulted in residual
systemic photosensitization (Lange et al., 1999). Hexaminolevulanic
acid is a derivative that avoids the systemic photosensitization.
Hexaminolevulanic acid has been approved widely for use in fluo-
rescence or “blue light” cystoscopy, also known as photodynamic
diagnosis, or PDD.
When blue light technology is used, small papillary tumors and
almost one-third more cases of CIS overlooked on cystoscopy are
identified (Fradet et al., 2007; Jichlinski et al., 2003; Schmidbauer
et al., 2004) (Fig. 136.7). In one study, 96% of all tumors were
detected with hexaminolevulinate (HAL) imaging compared with
77% with standard cystoscopy. Detection was improved for CIS (95%
vs. 68%), and papillary tumors (96% vs. 85%) (Jocham et al., 2005).
The clinical impact of improved tumor detection seems intuitive, and
prospective evidence has shown that this decreases recurrence rates
in patients who undergo HAL fluorescence cystoscopy compared
with controls (Denzinger et al., 2007; Filbeck et al., 2003; Gross-
man, 2007; Rink et al., 2013). The impact appears to persist for
at least 4 years. There may be an impact on progression, although
one study that examined this was underpowered to prove this trend
(Stenzl et al., 2010). Fluorescence cystoscopy can also be used in
the office setting with flexible cystoscopy (Fig. 136.8). Studies have
demonstrated that even with flexible cystoscopy about 20% more
recurrent papillary tumors and 34% more areas of CIS can be detected
3098 PART XIV  Benign and Malignant Bladder Disorders

Fig. 136.7.  White light cystoscopy reveals apparent normal-appearing mucosa juxtaposed with blue light
cystoscopy demonstrating visual evidence of bladder cancer. Blue light cystoscopy reveals accumulation
of hexaminolevulinate in the same area, ultimately found to contain non–muscle-invasive bladder cancer
(NMIBC). (Image courtesy Dr. Siamak Daneshmand.)

Fig. 136.8.  White and blue light cystoscopy of non–muscle-invasive bladder cancer (NMIBC) using flexible
cystoscopy after administration of hexaminolevulinate. (Image courtesy Dr. Siamak Daneshmand.)

using fluorescence cystoscopy (Daneshmand et al., 2017). Another
advantage of fluorescence cystoscopy is the ability to more accurately
assess thoroughness of TUR. This would allow for more complete
resection at the initial setting and reduce recurrence rates. A meta-
analysis of all the studies incorporating this technique suggests that
fluorescence cystoscopy can decrease recurrence up to 1 year and
beyond, but not all studies consistently demonstrate this finding
(Chou et al., 2017).
Narrow band imaging (NBI) is an optical image enhancement
technology intended to improve the visibility of blood vessels inherent
to neoplastic processes. NBI light is composed of two specific
wavelengths that are absorbed by hemoglobin; 415-nm light penetrates
only the superficial mucosal layers, whereas 540-nm light penetrates
more deeply. The combination allows improved visualization of
tumors and enables distinguishing blood vessels on and below the
surface from tumors. Several studies have been performed that reveal
that NBI is able to detect more papillary tumors as well as CIS (Xiong
et al., 2017). Initial studies suggest that about 13% more tumors
could be diagnosed by NBI (Herr and Donat, 2008). More tumors
were found using NBI compared with cystoscopy in 56% of cases.
False-positive rates of NBI, however, are approximately 60%. TUR
performed with NBI was also found to be more thorough, yielding
reduced recurrence rates after TUR (Naselli et al., 2010, 2012). A
more recent randomized trial conducted by Naito et al. (2016)
demonstrated that the recurrence rates after TUR performed under
white light cystoscopy and with NBI were no different. However,
short-term recurrence rates at up to 3 months were reduced in low-risk
tumors. This suggests that NBI-based resection may allow more
thorough resection of surface tumors but cannot alter the pattern
of recurrence in higher risk tumors.
Optical coherence tomography is a real-time imaging technology using
near-infrared light (890–1300 nm) to provide cross-sectional images of
biologic tissues. A small probe can be passed via cystoscope into bladder
to allow real-time examination of bladder tumors. This technology is
able to distinguish layers of urothelium and lamina propria as well
as muscularis propria and distinguish between benign and malignant
characteristics (Lerner and Goh, 2015). Early experience suggests more
than 90% sensitivity, specificity, and negative predictive value with regard
to detecting muscle invasion at time of cystoscopy (Lerner et al., 2008),
which may facilitate determining appropriate depth of resection.
Confocal laser endomicroscopy involves administration of fluores-
cein and use of a 488-nm low-power laser to scan the tissue section
of interest below the surface. Specific optical diagnostic criteria are
then used to characterize tissue at the micro-architectural and cellular
level to distinguish between normal urothelium, benign inflammatory
lesions, and low- versus high-grade tumors (Chen et al., 2014).
Enhanced cystoscopic techniques are now included in the AUA
guidelines (Chang et al., 2016) as techniques to be considered for
improving detection rates and for ensuring more complete TUR.
INTRAVESICAL THERAPY
Perioperative Intravesical Therapy
It is believed that tumor cell implantation immediately after
transurethral resection is responsible for many early recurrences,
 Chapter 136  Management Strategies for Non–Muscle-Invasive Bladder Cancer (Ta, T1, and CIS)
KEY POINTS: ENDOSCOPIC SURGICAL MANAGEMENT
• TURBT is performed to remove all visible tumors and to
provide specimens for pathological examination to
determine stage and grade.
• Repeat resection within 2 to 6 weeks is usually indicated
in patients with high-grade disease, especially if no muscle
was present in the initial TURBT.
• All suspicious lesions should be sampled, but random
biopsies are not required in low-risk patients.
• Office-based fulguration and observation may be applied
to certain low-risk patients.
• Fluorescence cystoscopy with 5-ALA derivatives and NBI
improves the ability to visualize inconspicuous tumors
and could reduce short- and long-term recurrence rates
after TUR.
and this has been used to explain the observation that initial tumors
are most commonly found on the floor and lower sidewalls of the
bladder, whereas recurrences are often located near the dome as a
result of “flotation” (Heney et al., 1981). Thus intravesical chemo-
therapy to kill such cells before implantation has been used for
decades (Klan et al., 1991; Zincke et al., 1983).
Mitomycin C (MMC) appears to be the most effective adjuvant
intravesical chemotherapeutic agent perioperatively, although epi-
rubicin is used in Europe and direct comparative studies are lacking
(Witjes and Hendricksen, 2008). Consistent with its proposed
mechanism of action to prevent tumor cell implantation, a single
dose administered within 6 hours lessens recurrence rates, whereas
a dose 24 hours later does not (Duque and Loughlin, 2000; Isaka
et al., 1992; Oosterlinck et al., 1993; Sekine et al., 1994; Solsona
et al., 1999), and maintenance therapy does not reduce the risk
further (Bouffioux et al., 1995; Tolley et al., 1996).
A meta-analysis of the use of perioperative chemotherapy found
that low-risk patients experience a drop in the odds of recurrence
from 48.4% to 36.7% at a median follow-up of 3.4 years. Patients
with multiple tumors experienced a 56% reduction in the odds of
recurrence. MMC, epirubicin, and pirarubicin significantly decreased
the recurrence of single and multiple tumors. Thiotepa did not show
the same benefit, but data were limited and some studies used diluted
strengths (Sylvester et al., 2004). The number needed to treat (NNT)
to prevent one recurrence in the meta-analysis was 8.5, so some
authors have suggested that intravesical chemotherapy reduces overall
cost of care by reducing the need for secondary resections. However,
subsequent studies have shown that the tumors prevented are primarily
smaller tumors that are often treated in the office or ambulatory
surgery setting (Berrum-Svennung et al., 2008). In addition, the
benefit appears limited to patients with low risk of recurrence
(Gudjónsson et al., 2009), so the economic impact regarding recur-
rences remains controversial if recurrences are treated in any manner
other than inpatient care (Lee et al., 2012; Rao and Jones, 2009).
Randomized trial data have demonstrated that immediate intravesical
instillation of mitomycin C reduces the risk of recurrence, even in
patients treated with ongoing adjuvant instillations (Bosscheiter et
al., 2018). Hence, level 1 evidence demonstrates that a single-dose
of mitomycin C or epirubicin instilled within 6 hours after resection
reduces tumor recurrence, particularly for the initial presentation
of a solitary papillary low-grade tumor.
Studies using post-TUR instillation of gemcitabine have yielded
mixed results. In one randomized study published by Böhle et al.
(2009), recurrence-free survival at 1 year was no different in patients
undergoing gemcitabine instillation vs saline. All patients in this
study underwent more than 20-hour irrigation of the bladder with
saline, thus raising the question of whether the continuous irrigation
of the bladder post TUR can be helpful in reducing recurrence rates
through mechanical extraction of floating cells. To this end, sterile
water irrigation (Moskovitz et al., 1987) and normal saline continuous
bladder irrigation have been evaluated and shown potential to reduce
tumor recurrences after TURBT (Onishi et al., 2017). In a more recent
3099
Fig. 136.9.  CT image taken from image of a 59-year-old male who received
perioperative administration of mitomycin C at time of transurethral resection
of bladder tumor in the setting of extravesical perforation. This patient sub-
sequently developed calcified, necrotic tissue associated with non-healing
bladder ulcer (as pictured in image with red arrow pointing to calcified region)
and ultimately required radical cystectomy with ileal neobladder secondary
to refractory symptoms.
phase III randomized trial completed by the Southwest Oncology
Group (SWOG), intravesical administration of gemcitabine was again
compared with saline in the immediate post-TURBT setting. In this
trial, reported by Messing et al. (2017), gemcitabine demonstrated
a 34% reduction in the likelihood of tumor recurrence with a very
favorable side-effect profile. Hence gemcitabine remains an alternative
option for perioperative intravesical chemotherapy.
The use of perioperative intravesical therapy is widespread in
Europe but has achieved less frequent adoption in the United States
(Madeb et al., 2009) potentially because of the cost, complexity,
and potential for side effects, combined with the fact that it has not
been shown to have adequate impact for recurrent, multiple, or
high-grade tumors (Sylvester et al., 2004). A more detailed analysis
of more than 2000 cases derived from 5 large practice sites in the
United States revealed that post-TUR instillation of chemotherapy
was used in an appropriate and judicious manner in up to 85% of
cases and avoided mainly because of suspicion of perforation in
many cases (Barocas et al., 2013).
Although local irritative symptoms are the most common
complications of postoperative instillation, serious sequelae and
rare deaths have also occurred, especially in patients with perfora-
tion during resection (Oddens et al., 2004). Other reported condi-
tions associated with intravesical chemotherapy (with perioperative
or multi-dose regimens) include chemical cystitis, cutaneous des-
quamation, decreased bladder capacity as a result of contractures,
calcified eschars, and complications or added difficulty of subsequent
cystectomy (Fig. 136.9; Cliff et al., 2000; Doherty et al., 1999;
Nieuwenhuijzen et al., 2003; Oddens et al., 2004; Shapiro et al.,
2006). Chemotherapy should be withheld in patients with extensive
resection or when there is concern about perforation.
BCG can never be safely administered immediately after TUR
because the risk of bacterial sepsis and death is high.
Intravesical Immunotherapy
Bacille Calmette-Guérin
BCG is an attenuated mycobacterium developed as a vaccine for
tuberculosis that has demonstrated antitumor activity in several
different cancers including UC (Morales et al., 1976). The original
regimen described by Morales included a percutaneous dose, which
3100 PART XIV  Benign and Malignant Bladder Disorders
KEY POINTS: PERIOPERATIVE INTRAVESICAL
THERAPY TO PREVENT TUMOR IMPLANTATION
• Single-dose intravesical chemotherapy administered within
6 hours of resection reduces recurrence of low-risk tumors
with significant impact in the setting of initial presentation
of solitary low-grade papillary tumors.
• The incremental benefit in patients with recurrent or
multiple tumors is limited.
• No benefit has been found in patients with high-grade
disease.
was discontinued after success with a similar intravesical regimen
by Brosman (1982).
BCG powdered vaccine is reconstituted with 50 mL of saline and
is routinely administered through a urethral catheter. Treatments
are typically started 2 to 4 weeks after tumor resection, allowing
time for re-epithelialization of the bladder after TURBT, thereby
minimizing the potential for intravasation of live bacteria (Lamm
et al., 1992). A urinalysis is usually performed immediately before
instillation to further confirm absence of infection or significant
bleeding to decrease the likelihood of systemic uptake of BCG.
In the event of a traumatic catheterization, the treatment should
be delayed for at least several days, depending on the extent of
injury. Active urinary tract infection is often considered an indication
to delay treatment until it has been managed; however, recent publica-
tions question the need to avoid BCG in the presence of asymptomatic
bacteriuria (Herr, 2012). After instillation, the patient should retain
the solution for at least 1 to 2 hours. Some clinicians have advocated
that the patient turn from side to side to bathe the entire urothelium,
but there is no scientific support for this practice. Fluid, diuretic,
and caffeine restriction before instillation limits dilution of the agent
by urine and facilitates adequate retention of the agent for 2 hours
(Lamm et al., 2000b). Patients are commonly instructed to clean
the toilet with bleach, although there is no demonstrable risk of
close contact infection.
Mechanism of Action
Intravesical immunotherapy results in a robust local immune
response characterized by induced expression of cytokines in the urine
and bladder wall and by an influx of granulocytes and mononuclear
and dendritic cells (Shen et al., 2008). The initial step appears to be
direct binding to fibronectin within the bladder wall, subsequently
leading to direct stimulation of cell-based immunologic response and
an antiangiogenic state. Numerous cytokines involved in the initiation
or maintenance of inflammatory processes including tumor necrosis
factor-α (TNF-α), granulocyte-macrophage colony-stimulating factor
(GM-CSF), interferon-γ (IFN-γ), and interleukin-1 (IL-1), IL-2, IL-5,
IL-6, IL-8, IL-10, IL-12, and IL-18 have been detected in the urine of
patients treated with intravesical BCG and other immunostimulatory
agents. Release of tumor necrosis factor–related apoptosis inducing
ligand (TRAIL) also appears to be a key event in propagation of
the BCG response and is associated with response to BCG (Ludwig
et al., 2004). The observed pattern of cytokine induction with
preferential upregulation of IFN-γ, IL-2, and IL-12 reflects induction
of a T-helper type-1 (Th1) response. This immunologic response
activates cell-mediated cytotoxic mechanisms believed to underlie
the efficacy of BCG and other agents in the prevention of recurrence
and progression (Bohle and Brandau, 2003). BCG may concomitantly
stimulate IL-10, resulting in the suppressive Th2 response. Overall,
response to intravesical immunotherapy may be limited if a patient
has an immunosuppressive disease or by advanced age (Joudi et al.,
2006a, 2006b). More recent data, however, suggest that BCG can be
used safely in patients who are immunosuppressed such as transplant
recipients and those on systemic steroid therapy without significant
increase in side effects or BCG sepsis (Herr and Dalbagni, 2013).
Response to BCG therapy may not be as robust as seen in patients
who are not similarly immunosuppressed.
Bacille Calmette-Guérin Treatment of Carcinoma in Situ
BCG is the most commonly used intravesical agent in the United
States, whereas intravesical chemotherapy is more commonly used in
other parts of the world. BCG is approved for intravesical treatment
of NMIBC by the US Food and Drug Administration (FDA). Before
the adoption of BCG intravesical therapy, CIS reportedly progressed
at an average rate of 7% per year (Zincke et al., 1985). The initial
tumor-free response rate is as high as 84% (Brosman, 1982; De
Jager et al., 1991; Hudson and Herr, 1995; Lamm et al., 2000a,
2000b, 2000c). Approximately 50% of patients experience a durable
response for a median period of 4 years. Over a 10-year period,
approximately 30% of patients remain free of tumor progression or
recurrence, so close follow-up is mandatory. The majority of these
occur within the first 5 years (Herr et al., 1992). Herr et al. (1989)
reported progression in 19% of initial responders at 5 years but
found the rate to be 95% in nonresponders—findings confirmed
by other investigators (Coplen et al., 1990; Harland et al., 1992). The
current AUA guidelines panel recommends BCG as the preferred
initial treatment option for high-risk bladder tumors and as a
potential option either up front or preferably after intravesical
chemotherapy for intermediate-risk tumors (Chang et al., 2016).
BCG has gained a preeminent role in North America on the basis
of higher efficacy reports compared with intravesical chemotherapy
(O’Donnell, 2007). BCG is more effective than intravesical mitomycin
C but only when comparing BCG induction + maintenance doses
versus a 6-week induction course of mitomycin alone. Furthermore,
intravesical BCG instillation is associated with reduced risk for
recurrence as well as progression (Chou et al., 2017), whereas
intravesical chemotherapy does not appear to affect progression.
BCG instillation is, however, associated with a greater risk of adverse
events including cystitis, dysuria, hematuria, and fever as compared
with other intravesical therapies (Chou et al., 2017). In more than
600 patients, there was a 68% complete response rate to BCG and
a 49% complete response rate to chemotherapy. In responders, 68%
of patients treated with BCG remained free of disease as compared
with 47% of patients receiving chemotherapy, on the basis of a
median follow-up of 3.75 years. The overall disease-free rates were
51% and 27%, respectively (Sylvester et al., 2005). More recently,
meta-analysis data have further identified that mitomycin C, doxo-
rubicin, epirubicin, and thiotepa are associated with a decreased
risk of recurrence. Unlike BCG, however, these intravesical chemo-
therapeutic agents do not appear to decrease the risk of progression
(Chou et al., 2017).
Bacille Calmette-Guérin Treatment of Residual Tumor
Intravesical BCG can effectively treat residual papillary lesions but
should not be used as a substitute for surgical resection. Investigators
have demonstrated a nearly 60% response by residual tumor with
intravesical BCG alone (Brosman, 1982; Coplen et al., 1990; Schell-
hammer et al., 1986).
Carcinoma of the mucosa or the superficial ducts of the prostate
can be adequately treated by BCG with a 50% tumor-free rate. A
limited TURP or fulguration can be effective in decreasing tumor
burden and facilitating exposure of the prostate surface to BCG
administration (Bretton et al., 1990; Schellhammer et al., 1995).
Bacille Calmette-Guérin Prophylaxis to Prevent Recurrence
Early single-center studies demonstrated an advantage in decreased
tumor recurrence of approximately 30% when a 6-week course of
BCG was administered after recovery from TURBT (Brosman, 1982;
Morales et al., 1992). In several larger series, tumor recurrence after
TURBT was reduced by 20% to 65%, for an average of approximately
40% (Herr et al., 1992; Krege et al., 1996; Melekos et al., 1993;
Pagano et al., 1991a, 1991b). A meta-analysis of 2000 patients with
Ta, T1, and/or CIS disease found that patients receiving maintenance
BCG had a statistically decreased rate of recurrence compared with
those receiving induction therapy alone (Han and Pan, 2006). A
subsequent reevaluation of the published data concluded that 3
 Chapter 136  Management Strategies for Non–Muscle-Invasive Bladder Cancer (Ta, T1, and CIS)
years of maintenance therapy was supported by the literature but
that patients with intermediate-risk disease may be equally managed
with 1 year of maintenance (Ehdaie et al., 2013). A more recent
meta-analysis further identifies a decreased risk of recurrence with
BCG administration (Chou et al., 2017).
The efficacy of BCG after TURBT for high-risk papillary disease
has been demonstrated in several series of T1 lesions, with recur-
rence rates of 16% to 40% and progression rates of 4.4% to 40%,
a substantial improvement compared with TUR alone (Cookson
and Sarosdy, 1992; Gohji et al., 1999; Herr, 1997; Hurle et al., 1999a,
1999b; Jimenez-Cruz et al., 1997; Pansadoro et al., 1995). Tumor
multiplicity and associated CIS were associated with increased risk
of progression. Substaging lesions on the basis of the presence or
absence of muscularis mucosae invasion in a series of 49 patients
did not improve prediction of recurrence (69% vs. 65%) or progression
(22% vs. 29%) after BCG therapy (Kondylis et al., 2000).
Impact of Bacille Calmette-Guérin on Progression
Although reports of the impact of BCG on tumor recurrence are
compelling, the greater need is the potential for impact on progression.
In 403 patients with CIS, BCG reduced the risk of progression by
35% compared with intravesical chemotherapy (Sylvester et al., 2002).
In a randomized trial of 86 patients with high-risk superficial
disease, Herr et al. (1988) demonstrated a greater delay in interval
progression for BCG patients versus TUR controls. In addition, the
cystectomy rate was significantly decreased for CIS patients treated
with BCG (11% vs. 55% for controls), and time-to-cystectomy was
delayed in the BCG group. However, only 27% of patients were alive
with an intact functioning bladder after follow-up over 10 to 15
years, so this apparent advantage is temporary in many cases (Cookson
et al., 1997). Available data suggest that BCG can delay progression
of high-risk bladder cancer, yet the long-term survival advantage is
not fully defined.
Nevertheless, meta-analyses have concluded that BCG reduces
the risk of progression. Progression at 2.5 years’ median follow-up
was reduced by 27% (9.8% for BCG vs. 13.8% for non-BCG) in one
(Sylvester et al., 2002) and by 23% (7.7% for BCG vs. 9.4% for
MMC) at 26-month median follow-up in another analysis (Bohle
and Bock, 2004). More recent meta-analysis data further identify
reduced risk of progression in patients treated with BCG with an
RR of 0.39 based on data from 4 trials (Chou et al., 2017). In each
meta-analysis the superior results with BCG were concentrated in
trials using BCG maintenance therapy. In contrast, no chemotherapy
trials have achieved a significant reduction in progression (Chou
et al., 2017; Grossman et al., 2008).
Determining Optimum Bacille Calmette-Guérin
Treatment Schedule
The optimal treatment schedule and dose for BCG have not been
established (Herr et al., 2011). In reality, several studies and AUA
guidelines suggest that a 6-week induction course alone is insuf-
ficient to obtain an optimal response in many patients and that
maintenance therapy is requisite (Chang et al., 2016; Lamm et al.,
2000a,b,c; Palou et al., 2001).
The average additional response to a second induction course
is 25% in those patients treated for prophylaxis and 30% in CIS
patients (Bohle and Bock, 2004; Bretton et al., 1990; Coplen et al.,
1990; Haaff et al., 1986; Kavoussi et al., 1988; Sylvester et al., 2002).
However, additional courses of BCG to treat refractory patients
after a second 6-week course are accompanied by a significant risk
of tumor progression in 20% to 50% of patients (Nadler et al.,
1994). Catalona et al. (1987) reported roughly a 7% actuarial risk of
progression with every additional course of BCG therapy. Response
to BCG at 6 months can be used as a predictor of prognosis,
with the number of patients developing progressive disease being
significantly higher among nonresponders (Orsola et al., 1998).
The Southwest Oncology Group (SWOG) reported the most
significant impact of maintenance therapy. Patients received a 6-week
induction course followed by 3 weekly instillations at 3 and 6
3101
months and every 6 months thereafter for 3 years. Estimated
median recurrence-free survival was 76.8 months in the mainte-
nance arm and 35.7 months in the control arm (P = 0.0001).
Average recurrence-free survival was 111.5 months in the control
arm and could not be estimated in the maintenance arm (P = 0.04).
Overall 5-year survival was 78% in the control arm and 83% in the
maintenance arm. No toxicities above grade 3 were observed, yet
only 16% of patients tolerated the full dose-schedule regimen.
Two-thirds of the patients who stopped BCG because of side effects
did so in the first 6 months, suggesting that the side effects do not
increase appreciably with additional time on therapy. Because of
the fact that the treatment group fared better despite most patients
having failed to complete the full course of therapy, the maximum
benefit may have been achieved earlier. Shorter maintenance
schedules and reduced dosages may accomplish the same results
with less toxicity (Lamm et al., 2000a).
More recent data from a randomized non-inferiority study pub-
lished by Oddens et al. (2013) clarify the use of different durations
of maintenance therapy based on risk stratification of the tumor. For
patients with intermediate-risk disease, a 1-year course of maintenance
BCG was administered at months 3, 6, and 12. In patients with
high-risk disease, the instillations were continued every 6 months
thereafter up to 3 years. Full dose and one-third dose of BCG were
tested in this four-arm trial. The results demonstrated that patients
with intermediate-risk disease benefited from 1 year of maintenance
therapy with full-dose BCG, whereas patients with high-risk disease
obtained the most benefit with 3 years of full-dose BCG therapy. Only
7.1% and 8.3% of patients who received 1 year of maintenance and
3 years of maintenance, respectively, had to discontinue treatment
because of side effects. For high-grade T1 lesions or CIS, maintenance
therapy has proven superior in multiple studies (Palou et al., 2001).
The determination of whether the optimal treatment schedule
should be as described in the SWOG study, monthly, or on some
other schedule remains undefined, and optimal duration of a
monthly maintenance schedule, if chosen, is not definitively
established. However, based on the trial reported by Oddens
et al., it appears that the SWOG regimen yields the best results
reported to date (Lamm et al., 2000a, 2000b, 2000c; O’Donnell,
2005, Oddens et al., 2013).
Several investigators have evaluated the potential for BCG dose
reduction (Martinez-Pineiro et al., 1995; Melekos et al., 1993; Morales
et al., 1992; Pagano et al., 1995). In general, a decrease in toxicity
with no statistical difference in efficacy has been noted in small
series (Hurle et al., 1996; Mack and Frick, 1995; Pagano et al., 1991b),
although multifocal and high-grade tumors may respond better to
full dosage (Martinez-Pineiro et al., 2002). Recent meta-analysis data
have not demonstrated clear differences between standard and lower
doses of BCG in recurrence, progression, or risk of mortality (Chou
et al., 2017). Some studies have shown an upregulation of the Th1
response with a lower dose of BCG. Lengthening of the instillation
interval may decrease side effects without loss of efficacy (Bassi et al.,
2000). Studies in Europe, where BCG inoculation for tuberculosis
is more common than in North America, suggest that the dose may
be safely reduced by half (Martinez-Pineiro et al., 2002). The difference
in response to doing so in immunologically naive North Americans
is unknown, but Morales et al. (1992) found a significant decrease
in response rates (67% vs. 37%), especially for patients with CIS in
combination with papillary tumors treated with the reduced dose.
The results from the EORTC trial reported by Oddens et al. (2013),
wherein worse responses were observed with one-third dose BCG
raises questions about the difference in efficacy between the full-dose
and reduced-dose BCG. Given the variability of this data, the most
recent AUA guidelines suggest there is insufficient evidence to
prescribe a particular strength of BCG (Chang et al., 2016).
Antibiotic therapy may have a beneficial effect in treating or
preventing systemic side effects of BCG therapy, yet it may also
inhibit the effectiveness of BCG therapy if it is given routinely for
urinary tract prophylaxis during a course of BCG therapy (Durek
et al., 1999a, 1999b). Quinolones were previously thought to affect
the viability of BCG (Durek et al., 1999b; Boxes 136.1 and 136.2).
However, subsequent randomized studies have demonstrated that
3102 PART XIV  Benign and Malignant Bladder Disorders
BOX 136.1 Contraindications to Bacille Calmette-
Guérin (BCG) Therapy
ABSOLUTE CONTRAINDICATIONS
Immunosuppressed and immunocompromised patientsa
Immediately after transurethral resection on the basis of the risk
of intravasation and septic death
Personal history of BCG sepsis
Gross hematuria (intravasation risk)
Traumatic catheterization (intravasation risk)
Total incontinence (patient will not retain agent)
RELATIVE CONTRAINDICATIONS
Urinary tract infection (intravasation risk)
Liver disease (precludes treatment with isoniazid if sepsis
occurs)
Personal history of tuberculosis (risk theorized but unknown)
Poor overall performance status
Advanced age
NO OR INSUFFICIENT DATA ON POTENTIAL
CONTRAINDICATIONS
Patients with prosthetic materials have not been shown to have
increased risk of infectious or other complications in limited
literature (Rosevear et al., 2010)
Ureteral reflux
Anti–tumor necrosis factor medications (theoretically predispose
to BCG sepsis)
a
Recent small series suggest this may not be an absolute contraindication
(Herr, 2012).
From Ehlers S: Why does tumor necrosis factor targeted therapy reactivate
tuberculosis? J Rheumatol (Suppl) 74:35–39, 2005.
short-term use of a quinolone antibiotic such as ofloxacin or pru-
lifloxacin for 24 to 48 hour post-BCG can reduce the cystitis-related
side effects of BCG instillation in up to 20% of patients with the
most significant reduction in side effects grade II or higher seen in
patients after the fourth instillation (Colombel et al., 2006; Damiano
et al., 2009). Post-instillation use of quinolones also reduced treatment
delays and discontinuations while not affecting recurrence or progres-
sion rates. Many urologists use this routinely as part of BCG instillation
protocol. A single dose of isoniazid (INH) or a 24-hour duration
of INH has been used before or around the time of BCG instillation
to reduce side effects. The results of this approach have been mixed
with one study demonstrating a reduction and another study showing
no change (Al Khalifa et al., 2000; van der Meijden et al., 2001).
Assessing the response to BCG is a critical component to successful
treatment with this agent. It is largely understood that the patient’s
immune response is a critical predictor for outcomes with BCG. As
such, Kamat et al. (2016) have developed a nomogram to predict
response to BCG based on a cytokine panel. This cytokine panel for
response to intravesical therapy (CyPRIT) evaluates a number of
urinary cytokines after BCG administration, with a nomogram based
on these findings demonstrating prediction of recurrence with AUC
of 86%. This and similar techniques have the potential to provide
a useful tool for predicting response to immunotherapy.
Interferon
IFNs are glycoproteins produced in response to antigenic stimuli.
These agents have multiple antitumor activities including inhibition
of nucleotide synthesis; upregulation of tumor antigens, antiangiogenic
properties; and stimulation of cytokine release with enhanced T- and
B-cell activation, as well as enhanced natural killer cell activity (Naitoh
BOX 136.2 Management of Bacille Calmette-Guérin
(BCG) Toxicity
GRADE 1: MODERATE SYMPTOMS <48 HOURS
Mild or moderate irritative voiding symptoms, mild hematuria,
fever <38.5°C
Assessment
Possible urine culture to rule out bacterial urinary tract
infection
Symptom Management
Anticholinergics, topical antispasmodics (phenazopyridine),
analgesics, nonsteroidal anti-inflammatory drugs
(Asymptomatic prostatic granulomas that occur after
BCG therapy can occasionally mimic prostate
cancer clinically and/or radiographically. There is
no evidence to support treatment in this setting [Suzuki
et al., 2013].)
GRADE 2: SEVERE SYMPTOMS AND/OR >48 HOURS
Severe irritative voiding symptoms, hematuria, or symptoms
lasting >48 h
All maneuvers for grade 1, plus the following:
Assessment
Urine culture, chest radiograph, liver function tests
Management
Consider dose reduction to one-half to one-third of dose when
instillations resume.
Treat culture results as appropriate.
Can also consider pre-treating with a single dose of isoniazid
before each subsequent instillation
Antimicrobial Agents
Administer isoniazid and rifampin orally until symptom
resolution.
Also use vitamin B6 or pyridoxine.
Do not use monotherapy.
Observe for rifampin drug-drug interactions (e.g., warfarin).
Monitor liver function tests.
GRADE 3: SERIOUS COMPLICATIONS (HEMODYNAMIC
CHANGES, PERSISTENT HIGH-GRADE FEVER)
Allergic Reactions (Joint Pain, Rash)
Perform all maneuvers described for grades 1 and 2, plus the
following:
Isoniazid and rifampin, depending on response.
Also use vitamin B6 or pyridoxine.
Solid Organ Involvement (Liver, Lung, Kidney)
Stop BCG instillations. Initiate antimycobacterial therapy with
isoniazid, rifampin. If symptoms persist, consult with
Infectious Disease specialist with expertise in anti-
tuberculous therapy. Can add ethambutol.
Cycloserine often causes severe psychiatric symptoms and is
to be strongly discouraged.
BCG is almost uniformly resistant to pyrazinamide, so this drug
has no role.
Consider prednisone when response is inadequate or for septic
shock (never given without effective antibacterial therapy).
 Chapter 136  Management Strategies for Non–Muscle-Invasive Bladder Cancer (Ta, T1, and CIS)
et al., 1999). Among several subtypes, IFN-α has been the most
extensively studied. It is most active in doses of at least 100 million
units, although optimal dose and administration schedule have yet
to be determined (Belldegrun et al., 1998; Torti et al., 1988).
IFN as a solitary agent is more expensive and less effective than
BCG or intravesical chemotherapy in eradicating residual disease,
preventing recurrence of papillary disease, and treating CIS (20% to
43% complete response). Its long-term efficacy for CIS is less than
15% (Belldegrun et al., 1998). A randomized trial demonstrated
CIS responses from 5% at low doses (10 million units) to as high
as 43% at high doses (100 million units) (Torti et al., 1988). As a
prophylactic agent, IFN alone demonstrated recurrence rates that
were inferior in general to those of BCG alone (from 60% to 16%)
(Glashan, 1990; Kalble et al., 1994). It has demonstrated limited
activity against T1 tumors (Malmstrom, 2001). However, it can
occasionally be effective in patients in whom BCG has failed (15%
to 20% complete response; see later).
IFN-α has also been studied in a combination treatment regimen
with either chemotherapy or BCG (Bercovich et al., 1995; Stricker
et al., 1996). There appeared to be additive effects with either
epirubicin or MMC. Several trials investigated the combination
of BCG and IFN and suggested the potential superiority of the
combination or the possibility of decreasing the dose of BCG,
which may reduce side effects. Initial work by O’Donnell et al.
(1999) reported a 63% disease-free rate at 12 months and 53%
at 24 months with use of combination therapy. A subsequent
randomized trial conducted in BCG-naive patients compared BCG
with BCG + interferon α-2b in a cohort of 670 patients (Nepple
et al., 2010). Patients were also secondarily randomized to receiv-
ing megadose multivitamins or recommended daily allowance of
multivitamins. There appeared to be no difference among all four
groups, suggesting that the addition of interferon α-2b as well as
megadose multivitamins did not significantly affect response to BCG.
At this point the main benefit of adding interferon α-2b to BCG
appears to be the fact that the dose of BCG can be reduced to a
third or lower without compromising the efficacy of the regimen.
Investigational Immunotherapeutic Agents
A number of novel agents have shown potential, but none has
reached clinical practice. Keyhole limpet hemocyanin (KLH) from
the hemolymph of the mollusk Megathura crenulata is a nonspecific
immune stimulant whose potential effectiveness in UC was identified
serendipitously (Jurincic et al., 1989; Olsson et al., 1974). Recent
work suggests continued promise for this agent but no clear supe-
riority to available agents (Lammers et al., 2012). Mycobacterial
cell wall DNA extract contains a mixture of immunostimulatory
DNA attached to antigenic cell wall. Phase II trial results indicate
success rates less than those achieved with BCG but with good
tolerability; however, no agent is commercially available (Morales
et al., 2001, 2009). A phase II single-arm study of this agent was
conducted in 129 patients by Morales et al. (2015), which demon-
strated an overall disease-free survival rate of 19% at 2 years. The
disease-free survival was higher (35%) in patients with papillary-
only tumors. A phase III study of the same agent was suspended
because of poor accrual. Only 75 patients of an anticipated 450
patients were enrolled, and no significant difference between groups
was noted.
IL-2 is highly expressed after BCG stimulation and is a key
component of the Th1 immune response. Preclinical data suggest a
potential benefit and little toxicity (Horinaga et al., 2005). Multiple
studies have documented the potential use of either intravesical IL-2
alone, with BCG, or with BCG and IFN (Shapiro et al., 2007). Preclini-
cal data identifying the efficacy of liposome-mediated intravesical
IL-2 with biologic response modifiers have elucidated long-term
T-cell memory against muscle-invasive bladder cancer and NMIBC
(Horiguchi et al., 2000; Larchian et al., 2000). Combination therapy
with BCG and intravesical interferon α-2b and IL-2 along with
granulocyte colony-stimulating factor has been shown to yield surpris-
ingly high response rates in patients who had previously failed
intravesical BCG therapy (Steinberg et al., 2017).
3103
KEY POINTS: IMMUNOTHERAPY
• Intravesical BCG has higher efficacy and side effects
compared with intravesical chemotherapy.
• BCG should be used cautiously for patients with low-risk
disease because of concern about side effects.
• Management of infectious complications of BCG is shown
in Box 136.2.
• BCG is the only agent shown to delay or reduce high-grade
tumor progression.
• The optimal dose and the treatment schedule for BCG are
undetermined, but results are better with maintenance
therapy, if tolerated.
• BCG is contraindicated in the setting of a disrupted
urothelium because of the risk of intravasation and
BCG sepsis.
Intravesical Chemotherapy
Induction therapy using chemotherapeutic agents instilled within
6 hours of TURBT has demonstrated a clear impact on recurrence
rates, as described earlier and are recommended in current clinical
guidelines (Chang et al., 2016). However, the role of chemotherapy
in the adjuvant setting is less clear compared with the efficacy of
BCG. A SWOG trial that compared doxorubicin and BCG showed
a 15% progression rate in patients receiving BCG compared with
a 37% progression rate in patients receiving chemotherapy (Lamm
et al., 1991). In addition, data have suggested that BCG with main-
tenance confers a lower risk of recurrence compared with mitomycin
C, doxorubicin, epirubicin, and thiotepa (Chou et al., 2017). Neverthe-
less, the risk of BCG infectious complications is nonexistent with
chemotherapy, leading many urologists to continue using these agents.
The main side effects of most chemotherapeutic agents appear to
be local such as cystitis and dermatitis if the agent comes in contact
with skin. On rare occasions systemic absorption can occur through
the skin or bladder, resulting in hematopoietic side effects or nausea.
The agents are summarized in Table 136.4.
Thiotepa
Thiotepa (triethylenethiophosphoramide) is the only chemothera-
peutic agent approved by the FDA specifically for the intravesical
treatment of papillary bladder cancer. It is an alkylating agent and
is not cell cycle specific. In controlled clinical trials (n = 950 patients),
it has been shown to significantly decrease tumor recurrence in 6
of 11 studies by up to 41% (mean decrease, 16%). Systemic side
effects can be seen because of its low molecular weight, resulting in
up to half of administered doses being absorbed, risking hemato-
poietic toxicity (Thrasher and Crawford, 1992). As such, most centers
have substituted its use with BCG or one of the aforementioned
chemotherapeutic agents.
Doxorubicin
Doxorubicin (Adriamycin) is anthracycline antibiotic that acts by
binding DNA base pairs, inhibiting topoisomerase II, and inhibiting
protein synthesis. In a review, doxorubicin demonstrated a 13%
to 17% improvement over TUR in preventing recurrence but no
advantage in preventing tumor progression (15.2% vs. 12.6%)
(Kurth et al., 1997). The principal side effect of intravesical doxo-
rubicin is chemical cystitis, which can occur in up to half of the
patients. Reduced bladder capacity has been reported in several series
(Thrasher and Crawford, 1992).
The doxorubicin derivative epirubicin decreases recurrence
compared with TUR alone by 12% to 15% (Oosterlinck et al.,
1993). This was demonstrated with a single, immediate, perioperative
dose, as well as in full 8-week courses of intravesical therapy. Epi-
rubicin is available for use in patients with UC in Europe and is
FDA approved but is unavailable for treatment of UC in the United
States. At least one study conducted in Japan combined epirubicin
3104 PART XIV  Benign and Malignant Bladder Disorders

TABLE 136.4  Comparisons Among Intravesical Agents

PERIOPERATIVE CYSTITIS DROPOUT CONCENTRATION

AGENT USE RISK GROUP (%) OTHER TOXICITY (%) AND DOSE

Doxorubicin Yes Low to 20–40 Fever, allergy, contracted 2–16 50 mg/50 mL

(Adriamycin) intermediate bladder, 5%
Epirubicin Yes Low to 10–30 Contracted bladder rare 3–6 50 mg/50 mL
intermediate
Thiotepa Yes Low to 10–30 Myelosuppression 2–11 30 mg/30 mL
intermediate 8%–19%
Mitomycin Yes Low to 30–40 Rash 8%–19%, 2–14 40 mg/20–40 mL
intermediate contracted bladder 5%
BCG No Intermediate 60–80 Serious infection, 5% 5–10 1 vial/50 mL
to high
Interferon No Salvage <5 Flulike symptoms 20% Rare 50–100 MU/50 mL
Gemcitabine Yes Salvage Mild Occasional nausea <10 1–2 g/50–100 mL
Valrubicin No Salvage Mild UTI, abdominal pain, <10 800 mg/55 mL
asthenia

BCG, Bacille Calmette-Guérin; UTI, urinary tract infection.

Modified from O’Donnell MA: Practical applications of intravesical chemotherapy and immunotherapy in high-risk patients with superficial bladder
cancer. Urol Clin North Am 32:121–131, 2005.

with lactobacillus casei, a probiotic agent commonly used in Japan
(Naito et al., 2008). Recurrence rates were reduced by 15% in patients
using lactobacillus casei as an oral supplement during epirubicin
instillation therapy.
Valrubicin
Valrubicin is a semisynthetic analogue of doxorubicin that was
approved by the FDA for treatment of BCG-refractory CIS in patients
who cannot tolerate cystectomy; the drug became available in 2009
in the United States (Greenberg et al., 1997; Grossman et al., 2008;
Sweatman et al., 1991). In a cohort of 90 patients with BCG-refractory
CIS, only 21% demonstrated a complete response (Steinberg et al.,
2000), so its use is not widespread.
Mitomycin C
MMC is an alkylating agent that inhibits DNA synthesis. The drug
is usually instilled weekly for 6 to 8 weeks at dose ranges from 20
to 60 mg. A meta-analysis of nine clinical trials compared its effect
on disease progression with that of BCG. With a median follow-up
of 26 months, 7.67% of the patients in the BCG group and 9.44%
of the patients in the MMC group developed tumor progression
(Bohle and Bock, 2004). More recently, Chou et al. (2017), in a
meta-analysis comparing MMC with BCG, identified no differences
between BCG and MMC with regard to recurrence risk; however,
BCG fared better in the subgroup of trials using maintenance (RR
0.79). MMC was also found to have higher risk of progression than
BCG in this same study. Another review found a 38% reduction
in tumor recurrence with MMC. This was not as effective as BCG
but was considered in most studies to make MMC a viable option
for reduction in recurrence (but not for progression) in light of
its lesser side effects (Huncharek et al., 2001).
Optimization of MMC delivery can result in halving of the recur-
rence rate in some studies. This can be achieved by eliminating
residual urine volume, fasting overnight, using sodium bicarbonate
to reduce drug degradation, and increasing concentration to 40 mg
in 20 mL (Au et al., 2001). The use of local microwave therapy in
conjunction with MMC, 20 mg/50 mL, reduced recurrence rates from
57.5% to 17.1% in a multicenter trial. A study using microwave
therapy with higher doses of 40 to 80 mg for 6 to 8 weeks in high-
grade bladder cancer found a recurrence-free rate of 75% at 2 years
(Gofrit et al., 2004; van der Heijden et al., 2004).
Electromotive intravesical MMC appears to improve drug delivery
into bladder tissue by four- to sevenfold (Di Stasi and Riedl, 2009;
DiStasi et al., 1999). The electromotive current is usually delivered
as a pulsed current of 40 to 60 mA/sec to a maximum of 20 mA
over 30 minutes through two cathode electrodes placed over the
gel-smeared skin of the lower abdominal wall. With this treatment
was reported reduction in recurrence rates with MMC from 58% to
31%, whereas patients in the BCG control arm had a 64% recurrence
rate (Di Stasi et al., 2003). A randomized trial conducted in patients
with primary and recurrent T1 urothelial carcinoma comparing BCG
alone with a combination of BCG alternating with electromotive MMC
reported lower recurrence and progression rates with the combination
treatment as well as better overall and cancer-specific survival (Di
Stasi et al., 2006). Peak plasma MMC was significantly higher in the
electromotive group, supporting its presumed mechanism of action.
More recent approaches have used the approach of heating the
bladder along with mitomycin instillation to incite a mild inflam-
mation of the bladder wall, which potentiates the action of mitomycin
but can also improve the effectiveness of BCG (DiStasi et al., 2011).
The interior of the bladder can be heated to a temperature of about
42°C using radiofrequency needles emerging from the tip of a urethral
catheter. The device is called the Synergo-RITE (Medical Enterprises
Group, Amstelveen, The Netherlands). The intravesical heating
enhances the absorption and activity of mitomycin C similar to
when the electric current is delivered transabdominally. Several single
arm studies have demonstrated encouraging results. Randomized
studies comparing chemohyperthemia (as it is termed) to plain
mitomycin instillation have demonstrated up to a threefold lower
recurrence rate with electromotive mitomycin or chemohyperthermia
(Colombo et al., 2011). However, a subsequent randomized study
by Arends et al. (2016), which compared electromotive mitomycin
to BCG instillation, demonstrated lower 2-year recurrence-free survival
in those receiving electromotive mitomycin, although this difference
was not statistically significant. There was an observed higher toxicity
in those receiving the electromotive MMC. Gan et al. (2016) have
also published work involving a combination protocol of BCG in
conjunction with electromotive MMC demonstrating promising
results of 87% initial complete response with 73% of their initial
first responders remaining disease free at 2 years.
An alternative method of delivering heated mitomycin C into the
bladder termed hyperthermic intravesical chemotherapy (HIVEC) can
be delivered using the Bladder Recirculation System (BRC) developed
by Combat Medical (Hertfordshire, United Kingdom). This method
 Chapter 136  Management Strategies for Non–Muscle-Invasive Bladder Cancer (Ta, T1, and CIS)
involves instilling a solution of mitomycin that is heated to 42°C
into the bladder in the form of a continuously recirculating irriga-
tion. Patients have been treated in a neoadjuvant fashion before
TUR and in an adjuvant fashion after TUR (Sousa et al., 2016).
Surprisingly, 62% of patients who received the treatment before
TUR had chemoablation of their tumors and a negative biopsy at
TUR. Of those who received the treatment in an adjuvant fashion,
2-year risk of recurrence was 12%. All treatments were focused on
patients with intermediate-risk disease. Although these results are
exciting, more data from randomized trials are needed before this
approach can be incorporated into the current treatment paradigm
(Jung et al., 2017).
Other Intravesical Therapeutic Agents
Gemcitabine and the taxanes paclitaxel and docetaxel have dem-
onstrated activity against metastatic bladder cancer (Calabro and
Sternberg, 2002). Intravesical gemcitabine can be safely administered
either weekly or twice weekly for six to eight treatments. Minimal
systemic absorption occurs through the bladder. Early small phase I
and phase II studies demonstrated reduction of recurrence of 39% to
70%, including modest efficacy in heavily pretreated BCG-refractory
patients (Maymi et al., 2004; O’Donnell, 2005). Di Lorenzo et al.
(2010) completed a randomized phase II trial using intravesical
gemcitabine versus re-induction course of BCG in patients who failed
one course of BCG and identified improved 2-year disease-free survival
but no significant difference in risk of progression or cystectomy
rates. An additional SWOG phase II trial evaluated gemcitabine
after two failed courses of intravesical BCG and identified a 2-year
disease-free survival rate of 21% (Skinner et al., 2013). As such,
gemcitabine appears to have a role, particularly in the setting of
previous BCG failure.
Taxanes have also been formulated into an active intravesical
treatment (Lu et al., 2004). Robins et al. (2017) have published a
phase II trial using nanoparticle albumin-bound paclitaxel in patients
with disease recurrence after BCG. This trial identified a complete
response rate of 36% and recurrence-free survival rate of 18% with
a median follow-up of 41 months. Although data remain limited,
these and other agents remain under investigation for patients with
BCG failure.
Apaziquone or EOquin is an indoloquinone that is derived from
mitomycin C. It has a rather high molecular weight of 288 kD and
hence does not easily penetrate the bladder epithelium. It is rapidly
cleared in the systemic circulation and requires activation by a
reductase that is found at relatively higher levels in bladder tumor
tissue compared with normal bladder epithelium. A phase II study
involving Ta/T1 marker lesions suggested an excellent pathological
response rate of 67% (van der Heijden et al., 2006). Side effects
mainly consisted of cystitis and hematuria with only 9% of patients
experiencing grade 3 toxicity. Subsequent phase III trials using this
agent for immediate perioperative instillation have not yielded
expected results and further trials are currently ongoing.
Combination Therapy
Combining mechanisms of different agents is a logical and often
successful approach to improve response rates for systemic therapy.
However, studies have not identified clear benefit to doing so in
intravesical therapy with a general theme of increased local side
effects with modest outcome improvement (Isaka et al., 1992; Sekine
et al., 1994).
There has been more interest in combination intravesical che-
motherapy using mitomycin and gemcitabine in sequence as well
as mitomycin and docetaxel. Breyer et al. (2010) demonstrated a
good response rate to sequential mitomycin and gemcitabine in
patients who were BCG refractory. This was confirmed in a larger
multi-institutional study in which a durable recurrence-free rate of
38% was found in a cohort of 47 patients (Lightfoot et al., 2014). In
this approach gemcitabine is instilled first at a dose of 1000 mg and
left in place for 60 to 90 minutes. After draining the gemcitabine, this
is followed by mitomycin C in the dose of 40 mg for another 60 to
3105
90 minutes. It is important to instill the mitomycin second because
it is a vesicant, and irritation caused by the mitomycin can make it
hard for the patient to retain the gemcitabine as well as resulting in
significantly greater local side effects. A combination of gemcitabine
and docetaxel has also been used for sequential intravesical instillation
(Steinberg et al., 2015). A 34% recurrence-free rate at 2 years has
been achieved in a pilot study of 45 patients, indicating that this
may be a promising approach. The main advantage of this regimen
compared with other combination intravesical therapies may be the
low incidence of side effects while maintaining a similar response. A
combination of chemotherapy and BCG was evaluated in prospective
trials by several investigators. The EORTC reported a 46% complete
response rate when a solitary marker tumor was intentionally not
resected and patients were subsequently given sequential MMC and
BCG (van der Meijden et al., 1996). In a study of 188 patients with
Ta and T1 lesions, no difference was seen with regard to recurrence,
progression, or side effects in those patients treated with BCG and
MMC compared with those treated with MMC alone. There was
actually a significantly longer disease-free interval in the BCG
monotherapy arm (55%) compared with the same combination
arm (45%) in another study of 314 patients (Malmstrom et al., 1999;
Solsona et al., 2002). Thus no clear advantage is obtained with
sequential therapy, or chemotherapy and BCG regimens in the
absence of electromotive current using any of the combinations
explored to date (Nieder et al., 2005; Rintala et al., 1995, 1996; Witjes
et al., 1998). Salvage approaches using sequential combination
chemotherapy using gemcitabine and mitomycin or docetaxel
may yield reasonable response and recurrence-free survival in
a subset of patients, although these data must be confirmed by
larger studies.
KEY POINTS: INTRAVESICAL CHEMOTHERAPY
• Intravesical chemotherapy has a clear impact on tumor
recurrence when immediately instilled after TURBT and in
the adjuvant setting. There is no clear evidence of an
impact on progression.
• Combinations of various chemotherapeutic agents and
chemotherapy combined with BCG have not demonstrated
major benefit combined with single-agent treatment, with
the exception of IFN.
• In general, side effects of chemotherapy tend to be less
common and less severe than those for BCG, but BCG is
more efficacious.
• Combination intravesical chemotherapy may have a role
in treating BCG refractory cancers
REFRACTORY HIGH-GRADE DISEASE
Recurrent or persistent disease after an initial 6-week course of BCG
has been traditionally referred to as BCG failure, although this term
has been poorly defined in the past. Persistent disease after BCG
therapy can be categorized as BCG refractory disease. Current
consensus is that BCG-refractory disease is defined in patients who
have persistent disease despite receipt of 2 induction courses of BCG,
induction plus maintenance (usually within 6 months), or intolerance
of BCG (Jarrow et al., 2014). BCG-refractory patients in particular
are an especially high-risk group and should be strongly considered
for immediate cystectomy if young and in generally good health
(Chang et al., 2016; Herr and Dalbagni, 2003). Additional intravesical
therapy for BCG refractory disease should be reserved for patients
who refuse or are too ill to undergo cystectomy or on defined
investigational protocols.
The necessity of biopsy to determine BCG response is unclear,
although it should be strongly considered in high-risk patients
to determine disease status at this key point in time. Urine cytol-
ogy can be useful in this setting. Dalbagni et al. (1999) reported
minimal usefulness of routine biopsy after BCG if cystoscopy and
urinary cytology were both negative. Whereas 5 of 11 patients with
3106 PART XIV  Benign and Malignant Bladder Disorders
erythematous bladder mucosa and positive cytology had positive
bladder biopsies, none of 37 with erythematous lesions and negative
cytology were positive, and only 1 in 13 patients with a normal
mucosa had a positive biopsy (Dalbagni et al., 1999). Other studies
have suggested that the value of routine post-BCG biopsy is limited
(Dalbagni et al., 1999). UroVysion FISH (Abbott Molecular, Chicago,
IL) conversion from positive to negative has been shown to correlate
with BCG response in single-center studies (Kipp et al., 2005; Whitson
et al., 2009).
Declaring failure may take up to 6 months because the response
rate for patients with high-grade bladder cancer treated with BCG
rose from 57% to 80% 3 to 6 months after therapy (Herr and
Dalbagni, 2003). This is particularly true for patients with CIS because
it appears that there is a delayed resolution of CIS that can occur
between 3 and 6 months. Clearly, the tumoricidal activity continues
for some period after cessation of therapy. This has obvious implica-
tions not only for declaring BCG failure and the need for subsequent
therapy, but also for interpretation of success rates of salvage protocols
if administered soon after therapy.
Management of Refractory High-Grade Disease
Although most urologists will administer an initial 6-week course
of intravesical therapy for high-risk patients, management of patients
with persistent disease after the first course is more complex.
Such patients are at increased risk of progression, which is
particularly likely in the event of early recurrence, progression
while on therapy, or multiple recurrences.
If the initial treatment was chemotherapy, a course of BCG
should be considered. BCG has demonstrated superiority to repeat
courses of chemotherapy in this setting because the latter will
lead to only an approximately 20% disease-free survival (Malmstrom
et al., 1999; Steinberg et al., 2000). For patients who have failed
BCG, a second course still gives a 30% to 50% response (Brake
et al., 2000; Pansadoro and De Paula, 1987). A second course of
BCG is recommended for patients with intermediate- or high-risk
disease if persistent or recurrent Ta disease or CIS is noted after
a single course of intravesical BCG in most recent AUA/SUO
guidelines (Chang et al., 2016). Patients who cannot tolerate BCG
for any reason may be considered for salvage chemotherapy, but the
risk of failure and progression is high.
Further courses of BCG or chemotherapy beyond two are not
recommended because they will fail 80% of the time, although
recent studies suggest some potential for newer agents (Skinner
et al., 2013). Rapid disease progression is common in such patients,
so salvage chemotherapy, investigational protocols, and IFN alone
or in combination with reduced doses of BCG may be appropriate
only for patients who are unwilling or unable to undergo surgery
even after being informed of their risks (Catalona et al., 1987).
Current guidelines recommend consideration of clinical trials as the
first option followed by radical cystectomy. Repeated attempts at
intravesical therapy beyond 2 years from initial tumor diagnosis
should be discouraged because there is a significant drop in cancer-
specific survival in patients with high-risk tumors (particularly T1)
who wait longer than this duration despite ultimate performance
of radical cystectomy (Herr and Sogani, 2001).
Role of Alternative Options for Refractory Disease
Photodynamic therapy (PDT) relies on a specific light interaction
with a photosensitized target tissue. This treatment is performed
by administering a photosensitizing agent such as porfimer sodium
(Photofrin) systemically or hexaminolevulinate (HAL) intravesically.
The patient is then given an intravesical treatment with light irradia-
tion. After excitation by light, the photosensitizer reacts with molecular
oxygen to form free radicals and reactive singlet oxygen to have
cytotoxic effect.
The response rate in CIS patients from combined series is 66%,
with a duration of 37 to 84 months (Jocham et al., 1989; Nseyo
et al., 1997, 1998; Walther, 2000). For patients with papillary disease,
an overall response rate of 51% has been achieved with a median
time to recurrence of 24 to 48 months (Naito et al., 1991; Nseyo
et al., 1997, 1998; Walther, 2000). PDT has been limited by significant
side effects such as bladder contracture or irritability (50%) and
dermal sensitivity (19%) (Naito et al., 1991; Nseyo et al., 1997,
1998; Uchibayashi et al., 1995). More recent trials have demonstrated
improved tolerability with HAL and an incoherent white light source
for irradiation. One such trial involved 2 treatments with HAL-PDT
6 weeks apart with 2 of 17 patients tumor free at 21 months (Bader
et al., 2013).
Research efforts have been directed at development of improved
photosensitizers and modifications in laser dosimetry (Kriegmair
et al., 1996a; Nseyo et al., 1997, 1998). HAL, a more lipophilic ester
of 5-ALA, generates a sensitizer called protoporphyrin IX that appears
more tumor specific, although clinical data are limited (Datta et al.,
1998). Radachlorin is composed of three chlorins and appears
promising, at least in the setting of BCG-refractory high-grade disease
(Lee et al., 2013).
Radiation therapy in the treatment of NMIBC is typically restricted
to individuals who refuse cystectomy after the failure of intravesical
therapy or who are unsuitable for major surgery (Kim et al., 2000).
A complete response to radiation therapy and TUR is attainable in
50% to 75% of patients, but the additional benefit of radiation to
TUR remains unclear (De Neve et al., 1992; Jansson et al., 1998;
Rozan et al., 1992). Five-year response rates are 44% to 60%. There
is no significant effect on CIS. Because of reports that up to 50% of
patients will develop progression and a high likelihood of death
(Rödel et al., 2001), there is a limited role for radiation therapy
other than for palliative purposes in this population. Combinations
of radiation and chemotherapy have shown promise but have not
reached widespread use (Gray et al., 2013).
Checkpoint inhibitors are a newer class of therapy under
investigation for use in NIMBC. These agents represent systemic
immunotherapy with a mechanism of action that involves disrupting
the interaction between programmed death ligand-1 (PD-L1), and
programmed cell death protein-1 (PD-1). In normal immune function,
the interaction between these receptors and their ligands regulates
T-cell activation and acts as an inhibitory signal in the generation
of immune response against a tissue. A number of malignancies,
including urothelial cell carcinoma, have been found to upregulate
this interaction to prevent immune response against tumor cells.
Over the past several years, monoclonal antibodies inhibiting this
interaction, and thereby activating cytotoxic T-cell function against
tumor cells, have been developed, with urothelial cell carcinoma
exhibiting susceptibility to such therapy (Mukherjee et al., 2018).
Several agents such as atezolizumab (PD-L1 inhibitor) have been
approved for patients with locally advanced or metastatic bladder
cancer who progressed after chemotherapy (Rosenberg et al., 2016).
Several additional agents including avelumab and durvalumab have
also been approved for this indication. Nivolumab and pembroli-
zumab are PD-1 receptor monoclonal antibodies that are approved
for similar indications in advanced disease, post-chemotherapy, and
for patients not eligible for cisplatin.
Given the response of urothelial carcinoma in advanced disease
as well as the long-standing role for BCG immunotherapy in NMIBC,
several current trials are aiming to assess the value of checkpoint
inhibitors in NMIBC. Current phase II clinical trials are ongoing in
patients with BCG-refractory disease evaluating the potential benefit
of atezolizumab, durvalumab, and pembrolizumab. Furthermore,
additional trials are underway using checkpoint inhibitors in combina-
tion with concurrent intravesical BCG (Mukherjee et al., 2018).
Although the efficacy of these agents in NMIBC remains under
investigation, checkpoint inhibitors represent a promising new line
of immunotherapy for this disease.
Role of “Early” Cystectomy
Despite local therapy, many cases of high-grade NMIBC will progress
to invasion and risk of cancer death. Although the initial response
rate to BCG therapy in CIS patients can be above 80%, patients in
whom treatment fails will have a 50% chance of disease progression
and potential for disease-specific mortality (Catalona et al., 1987;
 Chapter 136  Management Strategies for Non–Muscle-Invasive Bladder Cancer (Ta, T1, and CIS)
KEY POINTS: MANAGEMENT OF
REFRACTORY DISEASE
• Patients who experience failure of an initial course of
intravesical therapy after TURBT are at high risk of
recurrence or progression.
• Failure of initial chemotherapy or BCG is most
appropriately treated with a subsequent course of BCG
because its efficacy in this setting is significantly greater
than that of chemotherapy.
• After failure of a second course of intravesical therapy,
patients can be enrolled in clinical trials of new agents,
consider combination intravesical therapy, or proceed to
cystectomy.
Nadler et al., 1994). Early (3-month) failure for T1 tumors after
BCG is associated with an 82% progression rate, compared with a
25% progression rate in patients who do not experience treatment
failure at 3 months (Herr et al., 1997; Herr, 2000a). Up to 20% of
patients with CIS die of UC within 10 years (Herr et al., 1989); each
occurrence of T1 tumors is associated with a 5% to 10% chance of
metastasis (Herr and Sogani, 2001), and residual tumor found on
repeat resection in these patients is associated with an 82% chance
of development of muscle invasion (Herr et al., 1997). These data
offer compelling evidence of the potential to underestimate disease
status in high-risk patients.
Cookson et al. (1997) reported that 27% of high-risk patients
treated initially with aggressive intravesical therapy did well and
died of other causes, and the same low number survived with an
intact, functioning bladder 15 years after diagnosis. However,
approximately half of patients experienced progression, and one-third
died of their disease. In contrast, patients who undergo immediate
cystectomy for clinical T1 tumors benefit from more accurate
pathological staging in addition to a 10-year disease-free survival
of 92%, compared with 64% of those with clinical T1 tumors
who were found to actually have muscle invasion at the time of
cystectomy (Bianco et al., 2004).
Despite the benign connotation of the term superficial formerly
applied, up to 50% of patients with presumed non–muscle-invasive
high-grade disease who undergo cystectomy will actually be found
to have muscle-invasive disease. Such procedures have traditionally
been termed early cystectomy on the basis of the fact that they are
performed before the traditional surgical indication of documented
muscle invasion. Up to 15% will already have micrometastases (Chang
and Cookson, 2005) and a delay in cystectomy of even 12 weeks is
associated with poorer survival; therefore some of these procedures
do not seem to be early enough (Chamie et al., 2013; Sanchez-Ortiz
et al., 2003).
The risk of progression must be weighed against the risk, morbidity,
and impact on quality of life for cystectomy. Thus a reasonable goal
may be, as termed by Chang and Cookson (2005), “timely” cys-
tectomy for patients at risk.
Ten-year survival after cystectomy for non–muscle-invasive cancer
can range from 67% to 92% (Amling et al., 1994; Freeman et al.,
1995). However, despite the bias that substantial progression can
be averted with the benefit of early detection and close surveillance
in patients whose tumors are identified before muscle invasion, it
appears that such patients who progress to having muscle invasion
may have a poorer prognosis than do those who have muscle-
invasive disease on initial presentation (Lee et al., 2007; Schrier
et al., 2004). Thus overconfidence in disease control status with
high-risk patients on surveillance creates a false sense of security.
The AUA guidelines suggest cystectomy as the first option for
patients with refractory high-grade disease after an initial course
of intravesical therapy (see later). Nevertheless, fewer than one in
five American urologists surveyed stated that they would recom-
mend cystectomy for their patients with CIS refractory to two
courses of intravesical BCG, a group with an 80% risk of failure
or progression (Joudi et al., 2006a). Cystectomy in that setting,
3107
or for persistent high-grade papillary disease after two courses
of intravesical therapy, is the standard of care and should not be
considered “early.”
The role of surgical approaches involving potential oncologic
concessions such as seminal and nerve-sparing cystectomy in such
patients theoretically at lower risk of recurrence compared with
patients with muscle invasion remains unknown (Hautmann and
Stein, 2005). The availability of neobladder for less disfiguring urinary
diversion has been reported to decrease the delay in treatment of
such patients, potentially leading to significantly improved disease-free
survival (Hautmann and Paiss, 1998). The impact on disease outcomes
is unproven.
Cystectomy should also be considered in patients whose cancer
cannot be reasonably controlled through resection: bulky tumors,
inaccessible because of a large bladder or urethral stricture disease,
or otherwise not amenable to safe removal endoscopically.
In summary, radical cystectomy offers the most accurate patho-
logical staging option and should be strongly considered for
patients with NMIBCs that are high grade and invading deeply
into lamina propria, exhibit lymphovascular invasion, are associ-
ated with diffuse CIS, are in diverticula, substantially involve the
distal ureters or prostatic urethra, are refractory to initial therapy,
or are too large or anatomically inaccessible to be removed in
their entirety endoscopically. It can also be used in patients who
understand the risks and benefits of bladder preservation versus
cystectomy and request definitive therapy (Stein, 2003). Current
AUA guidelines suggest radical cystectomy in patients who are fit
for surgery and have persistent high-grade T1 disease on repeat
resection, or T1 tumors with associated CIS, LVI, or variant histolo-
gies. These same guidelines also suggest cystectomy in high-risk
patients with persistent or recurrent disease within 1 year after
treatment with two induction cycles of BCG or BCG maintenance
(Chang et al., 2016). Partial cystectomy has limited data but may
be a bladder preservation option in appropriately selected patients,
between the extremes of TURBT combined with intravesical therapy
and radical cystectomy.
KEY POINTS: EARLY CYSTECTOMY
• Patients at high risk for progression should be considered
for cystectomy.
• Failure to respond to an initial course of intravesical
therapy is occasion to reconsider cystectomy.
• Failure to respond to a second course is an indication for
immediate cystectomy unless contraindicated or the
patient chooses to pursue clinical trials or newer proven
intravesical options if evidence builds for their use.
SURVEILLANCE AND PREVENTION
Although bladder cancer is less common than prostate cancer,
expenditures are almost twice as high for bladder cancer because of
its chronic nature and the need for long-term surveillance. According
to the Agency for Healthcare Research and Quality, annual expen-
ditures were $2.2 billion in 2003 for bladder cancer versus $1.4
billion for prostate cancer (Donat, 2003). A significant portion of
this cost is associated with surveillance (Hedelin et al., 2002).
Surveillance strategies for UC recurrence have historically relied
on the diagnostic combination of cystoscopy and urinary cytology.
In clinical practice, only 40% of patients actually comply with a
standard surveillance protocol (Schrag et al., 2003). Although the
accuracy of both tests relies on subjective and operator-dependent
interpretation of visible findings, their traditional presumed status
as the gold standard has been widely accepted (Brown, 2000). The
timing and frequency of surveillance cystoscopy, cytology, and upper
tract imaging can be varied based on risk of recurrence and progres-
sion. To aid urologists in determining this risk for patients, several
models and risk stratification algorithms exist, including AUA/SUO
guideline stratification outlined in Table 136.2, and EORTC risk
tables, which take into account number of tumors, tumor size, prior
3108 PART XIV  Benign and Malignant Bladder Disorders

TABLE 136.5  2016 AUA/SUO Guideline Suggested Surveillance Strategies

RISK TUMOR STATUS CYSTOSCOPY SCHEDULE UPPER TRACT IMAGING

Low Solitary Ta low grade 3 mo after initial resection Not necessary unless hematuria present
Annually beginning 9 mo after initial surveillance
if no recurrence
Consider cessation at 5 or more years
Consider cytology or tumor markers
Intermediate Multiple Ta low grade Every 3–6 mo for 1-2 yr Consider imaging at 1- to 2-yr intervals,
Large tumor Every 6–12 mo for subsequent 2 yr especially for recurrence
Recurrence at 3 mo Annual cystoscopy thereafter Imaging for hematuria
Consider cytology or tumor markers
Restart clock with each recurrence
High Any high grade Every 3–4 mo for 2 yr Imaging annually for 2 yr, then consider
(including CIS) Semiannually for 2 yr lengthening interval
Annually for lifetime
Cytology at same schedule
Consider tumor markers
Restart clock with each recurrence

CIS, Carcinoma in situ.

Modified from Chang et al.: Diagnosis and treatment of non-muscle invasive bladder cancer, AUA/SUO Guideline, 2016.

recurrence rate, T stage, CIS, and grade (Sylvester et al., 2006). Using
these risk stratification systems surveillance can be tailored to
individual patients, and a summary of suggested surveillance protocols
consistent with most recent AUA/SUO guidelines is provided in
Table 136.5.
Cystoscopic Surveillance
Office-based cystoscopy offers rapid, relatively painless visual access
to the urothelium. Papillary tumors arising from the smooth bladder
surface are readily identified. CIS is classically described as a velvety
red mucosal patch, although the reliability of such findings is less
clear. Nevertheless, for office-based diagnosis it allows identification
of the site and characteristics of most tumors. There is a high positive
predictive value with cystoscopy because most lesions believed
to be malignant are proven so pathologically. The endoscopic
appearance cannot reliably predict tumor stage or grade, although
sessile morphology and/or the presence of necrosis suggests
high-grade disease likely to be invasive.
Cystoscopy is usually performed in the outpatient setting, often
using digital flexible cystoscopes in most settings. Complete visualiza-
tion of the bladder mucosa is possible in a matter of seconds in
most patients. Using the same technology for flexible cystoscopy as
described earlier for HAL fluorescence rigid cystoscopy, phase II
studies have had mixed results but suggest that office-based fluores-
cence cystoscopy can improve the detection of CIS and papillary
tumors (Loidl et al., 2005; Witjes et al., 2005).
The majority of men and women tolerate office-based cystoscopy
with minimal discomfort. Intraurethral injection of local anesthetics
is almost universal among urologists. Data from randomized
trials are contradictory (Palit et al., 2003; Rodriguez-Rubio et al.,
2004) and one meta-analysis indicated no benefit (Patel et al.,
2008b), whereas another indicated there was a benefit in pain
reduction when anesthetic containing lubricating gel was used
(Aaronson et al., 2009). Two recent studies actually found that pain
experience was higher with the use of local anesthetics than in patients
cystoscoped using aqueous lubricant alone (Chen et al., 2005; Ho
et al., 2003). Use of a video monitor allows patients to see and
understand the findings, theoretically distracting them from any
discomfort. Men who are able to do so tolerate the procedure with
approximately 50% less pain than those who cannot see their findings
on the monitor (Patel et al., 2007). Instillation of anesthetic gel into
the urethra has not been found to be of significant benefit in women,
probably because of the straighter urethra (Patel et al., 2008a).
The bladder should be emptied before cystoscopy. Aspiration
with use of a 60-mL syringe attached to the irrigant port is occasionally
necessary during the procedure. This can further lessen clouding. A
systematic approach is mandatory to ensure that all urothelium is
visualized.
The use of air cystoscopy, as opposed to fluid instillation, has
also been evaluated and found to potentially aid in visualization
during active hematuria (Ciudin et al., 2013) and may provide a
viable alternative in settings where sterile fluid irrigant is unavailable
(Dutta et al., 2017).
Attempts have been made to modify the previously described
surveillance schedule with use of decision analysis tools (Abel, 1993;
Kent et al., 1989). Several authors recommend termination of surveil-
lance at 5 or more years for low-risk patients (Haukaas et al., 1999).
However, the actual cost of surveillance cystoscopy was responsible
for only 13% of the expenditures for bladder cancer care in one
study, so the financial opportunity may be limited for such efforts
(Hedelin et al., 2002; Schoenberg et al., 2000). In addition, the risk
of recurrence and potential for progression exists beyond this period.
Reports of late recurrences of high-grade cancer years after the original
tumor temper some authors’ enthusiasm for terminating surveillance
at any point (Leblanc et al., 1999; Morris et al., 1995; Thompson
et al., 1993; Zieger et al., 2000). The AUA guidelines recommend
cystoscopic surveillance based on risk stratification of the tumor
into low-, intermediate- and high-risk categories. The recommended
surveillance schedule is shown in Table 136.5. Current AUA guidelines
indicate that surveillance beyond 10 years can be decided on a case-
by-case basis after a discussion between the patient and the urologist
(Chang et al., 2016).
Other investigators have examined the predictive impact of
early or multiple recurrences and how this may affect surveillance
(Holmäng et al., 1995; Parmar et al., 1989; Reading et al., 1995).
Tumor recurrence on initial 3-month cystoscopy and number of
tumors on initial resection (single or multiple) provide the most
predictive information with regard to recurrence in several studies.
Absence of recurrence on the 3-month surveillance cystoscopy in
patients with Ta low-grade tumors is associated with recurrence
rates so low that annual cystoscopy appears safe even at that point
(beginning 12 months after the initial resection) (Fitzpatrick et al.,
1986; Frydenberg et al., 2005; Olsen and Genster, 1995). Finally,
 Chapter 136  Management Strategies for Non–Muscle-Invasive Bladder Cancer (Ta, T1, and CIS) 3109

patients with a negative cystoscopy and a negative UroVysion assay
(see later) are at low risk of recurrence in the following 6 to 12
months, creating opportunity to individualize the surveillance
schedule (Sarosdy et al., 2002).
Urine Cytology
Cytology involves microscopic evaluation of stained cellular smears
from the urine. Unlike tumor markers, urinary cytology represents
a pathologist’s interpretation of the morphologic features of shed
urothelial cells rather than an objective laboratory test. Poor cellular
cohesion in high-grade tumors, especially CIS, enhances the yield.
Its high specificity is the most important feature of cytology because
a positive reading regardless of cystoscopic or radiographic findings
suggests the existence of malignancy in the vast majority of patients.
Even in the setting of UC, of patients with a negative workup
(cystoscopy and upper tract imaging) with a persistently positive
cytology, 40% were found to have genitourinary cancer within 24
months (Nabi et al., 2004).
Although cytology has traditionally been believed to have high
sensitivity for high-grade cancer, recent studies suggest that only
58% of bladder tumors are identified using cytology. Its low sensitivity
is not limited to low-grade tumors because only 71% of high-grade
cancers were identified. Cumulative data from series published
after 1990 reported that cytology actually identified (using the
older grading system) 11% of grade 1, 31% of grade 2, and only
60% of grade 3 tumors (Halling et al., 2000). In contrast, they
observed that these recent findings were well below those reported
before 1990, when the sensitivity of cytology was 94% for grade 3
tumors, but could find no explanation for this deterioration. These
findings are supported by numerous other studies and emphasized
by a recent multicenter study involving several institutions noted
for bladder cancer expertise that found cytology had an overall
sensitivity of 15.8% (Grossman et al., 2005).
Thus cytology has high specificity but low sensitivity for high-
grade and low-grade tumors, including CIS.
Benign conditions of the urinary tract such as stones, infection,
inflammation, hematuria, and cystoscopy can cause a false-positive
reading. A laboratory-based, quantitative immunoassay and a qualita-
tive point-of-care test are available. The sensitivities and specificities
range from 68.5% to 88.5% for sensitivity and from 65.2% to 91.3%
for specificity (Liou, 2006). A multi-institutional trial involving 1331
patients showed that, overall, the NMP22 was more sensitive than
cytology but less specific. Sensitivities were 50% and 90% for
noninvasive and invasive cancer, respectively, with an overall sensitivity
of 55.7%. Overall specificity was higher for cytology at 99.2%
compared with NMP22 at 85.7%. The sensitivity of cystoscopy in
this study was 88.6%, but when combined with NMP22, this increased
to 93.7% (Grossman et al., 2005).
UroVysion (Abbott Molecular, Des Plaines, IL) is a cytology-based
test that uses FISH of DNA probes or labels specifically chosen to
identify certain chromosomal foci. Probes to identify aneuploidy of
chromosomes 3, 7, and 17 are combined with a probe to the 9p21
locus. Probes can be developed to identify essentially any locus, but
this combination has the best sensitivity and specificity (Halling et al.,
2000). Cumulative data from comparative studies show sensitivity
for cytology compared with FISH of 19% versus 58% for grade
1, 50% versus 77% for grade 2, and 71% versus 96% for grade
3. Similar findings occurred by stage, wherein cytology compared
with FISH sensitivity was 35% versus 64% for Ta, 66% versus 83%
for T1, and 76% versus 94% for muscle-invasive carcinoma (Jones
et al., 2006; Fig. 136.10).
Notably, cytology detected only 67% of patients with CIS versus
100% detection by FISH in comparative studies. UroVysion has the
highest specificity of the available tumor markers. It will, however,
detect chromosomal changes before the development of phenotypic
expression of malignancy, so it leads to an “anticipatory positive”
reading in some patients. Such readings are often not false positives
and will lead to identification of clinical tumors within 3 to 15

Tumor Markers
Many attempts have been made to develop a UC biomarker test to
complement or replace urinary cytology. Most of these have had
adequate sensitivity but poor specificity, resulting in substantial
false-positive readings, creating the need for further diagnostic testing.
Current urinary markers have been developed to detect tumor-
associated antigens, blood group antigens, growth factors, cell cycle
and apoptosis, and extracellular matrix proteins. The most significant
issue limiting widespread adoption of tumor markers is the lack of
prospective data to support their impact on prognosis or disease
management (Lokeshwar et al., 2005).
The qualitative point-of-care test BTA stat (Polymedco, Cortlandt
Manor, NY) and the quantitative BTA TRAK (Polymedco) assay detect
human complement factor H–related protein. The overall sensitivity
of these tests ranges from 50% to 80%, whereas the specificity is
between 50% and 75%. These tests are more sensitive than cytology
particularly for low-grade tumors, but their results can be falsely positive
in patients with inflammation, infection, or hematuria (Liou, 2006).
ImmunoCyt (DiagnoCure, Saint Foy, Canada) is a hybrid of
cytology and an immunofluorescence assay. Three fluorescent-labeled
monoclonal antibodies are targeted at a UC variant of carcinoem-
bryonic antigen and two bladder mucins. Sensitivity and specificity
are reported to be 86% and 79%, respectively. The assay has not
been shown to be affected by benign conditions, but interpretation
is complex and operator dependent (Têtu et al., 2005; Toma et al.,
2004). This test may be helpful in adjudicating atypical cytology
because it has a high negative predictive value in this setting (Odisho
et al., 2013).
The NMP22 BladderChek Test (now marketed as the Alere NMP22 Fig. 136.10.  An abnormal enlarged cell (lower right) demonstrates three
BladderChek, Alere, St. Louis, MO) is based on the detection of copies of chromosome 3 (red), chromosome 7 (green), and chromosome
nuclear matrix protein 22, part of the mitotic apparatus released 17 (aqua) on use of fluorescence in situ hybridization. Homozygous deletion
from urothelial nuclei on cellular apoptosis. The protein is elevated of band 9p21 locus (yellow) is also present. (Courtesy Raymond Tubbs, MD,
in UC, but it is also released from dead and dying urothelial cells. Department of Laboratory Pathology, Cleveland Clinic Foundation.)
3110 PART XIV  Benign and Malignant Bladder Disorders
months in the majority of cases (Sarosdy et al., 2002). Moreover,
patients testing negative are unlikely to experience tumor recurrence
in less than 1 year (Yoder et al., 2007). Previous studies have suggested
that a persistently positive UroVysion FISH after BCG may predict
a poor response to BCG with higher likelihood of recurrence and
progression (Kamat et al., 2012). Thus the use of UroVysion FISH
may allow identification of patients at risk of recurrence versus those
unlikely to develop recurrence, and subsequent individualizing of
surveillance and treatment protocols.
UroVysion has also been shown to clarify equivocal findings in
patients with atypical or negative cytology (Skacel et al., 2003). It
is not affected by hematuria, inflammation, or other factors that can
cause false-positive readings with some tumor markers, so it appears
to be useful as a marker of BCG response (Kipp et al., 2005; Whitson
et al., 2009). “Non-diagnostic” UroVysion reports identifying limited
cellularity or positive cells at numbers below defined standards can
be regarded as negative and are not associated with increased risk
of bladder cancer recurrence in the future compared with expectations
with “normal” readings (Nguyen et al., 2009).
CxBladder Monitor is a noninvasive urine monitoring test using
gene expression and clinical patient data to generate a test to assess
for evidence of urothelial carcinoma. This test has been shown to
outperform other studies such as cytology and NMP22 with a sensitiv-
ity of 91% and negative predictive value of 96% (Lotan et al., 2017).
A retrospective study suggests that a multiplex of eight biomarkers
in combination may improve performance compared with currently
available markers if validated in further studies (Rosser et al., 2013).
The usefulness of tumor markers and the choice of which one
to use is not clear at this time. For example, if indication for biopsy
in the operating room is the end point, then high specificity is
desired to limit the number of negative biopsies. On the other hand,
if increasing the interval of cystoscopic surveillance is the end point,
then high sensitivity, particularly for high-grade tumors, is desired.
Defining that a patient has a low likelihood of recurrence within
the following year can allow individualization of surveillance protocols
(see Table 136.5; Grossman et al., 2006).
Current AUA guidelines discourage the use of urinary markers
to replace cytology for surveillance of NMIBC. They do, however,
suggest consideration of urinary markers to assess response to
intravesical therapy as well as for the adjudication of atypical or
equivocal cytology results (Chang et al., 2016).
Extravesical Surveillance
The proportion of patients developing upper tract UC after treatment
of non–muscle-invasive disease has been reported as 0.002% to
2.4% over intervals of 5 to 13 years (Holmäng et al., 1995; Oldbring
et al., 1989; Sadek et al., 1999; Shinka et al., 1988), although the
risk increases substantially over time to as high as 18% in very
high-risk populations (Herr et al., 1997). Synchronous tumors were
detected in no patients (0) with grade 1 (using the prior grading
system) tumors, 1.1% with grade 2, and 1.3% with grade 3, as well
as 0 for low-grade Ta and 7% for T1 (Herranz-Amo et al., 1999).
The Surveillance, Epidemiology, and End Results (SEER) database
showed that only 0.8% of bladder cancer patients develop sub-
sequent upper tract tumors, so surveillance is of limited value
unless the patient has hematuria or a high-grade tumor, especially
if it is near the ureteral orifice (Wright et al., 2009). In a review of
591 patients with median follow-up of 86 months, upper tract
recurrence was 0.9% in low-risk patients (solitary, low-grade, low-stage
Ta/T1), 2.2% in patients at intermediate risk (recurrent or multifocal
disease), and 9.8% in high-risk patients including intravesical
chemotherapy failures (Hurle et al., 1998). AUA guidelines suggest
that clinicians should not perform routine surveillance upper
tract imaging in asymptomatic patients with a history of low-risk
NMIBC. In the setting of intermediate- or high-risk patients,
guidelines suggest consideration of surveillance upper tract imaging
at 1- to 2-year intervals, but there are few data evaluating the
benefit of such imaging (Chang et al., 2016).
Multiphasic CT urography has become the preferred technology
for the evaluation of hematuria, but its role in the evaluation of
patients with NMIBC has not been extensively reported (Davis et al.,
2012; Herts, 2003). Magnetic resonance urography and renal ultra-
sound are potential alternatives in select patients. Retrograde ure-
teropyelography represents an additional alternative option to image
the upper tracts in patients with NMIBC, particularly in those unable
to undergo CT urography secondary to contrast allergies or renal
insufficiency. Although this does require procedural instrumentation,
it can often be done in the same setting with TURBT.
Although infrequent, the appearance of upper tract disease is
associated with mortality rates of 40% to 70%. Patients with high-
risk disease treated with BCG experience upper tract recurrence risk
of 13% to 18% (Herr et al., 1997; Miller et al., 1993). The risk for
recurrence in this population appears greatest over the first 5 years
after treatment (median time to detection, 56 months) yet persists
at least 15 years.
Selective cytology of the upper tract may increase the yield
of upper tract lesions detected, but, in the presence of a bladder
tumor, selective upper tract cytology may be falsely positive and
is not recommended for most patients (Sadek et al., 1999; Zincke
et al., 1983).
Secondary tumor involvement of the prostatic urethra and
ducts by UC may be detected in 10% to 15% of patients with
high-risk non–muscle-invasive disease within 5 years and in 20%
to 40% within 10 years (Donat, 2003). Patients who have refractory
disease are at risk for extravesical recurrence in the prostatic fossa
in approximately one-third of cases, 44% of which are fatal (Herr
et al., 1988). Involvement of the prostatic ducts by low-grade UC
is usually be managed by complete TURP for disease eradication
and to facilitate contact of intravesical therapy to the prostatic urethra.
Involvement of the ducts by high-grade disease is best managed by
radical cystoprostatectomy, and consideration of urethrectomy should
be made, especially if tumor is present near or at the surgical margin
(Liedberg et al., 2007).
In summary, surveillance strategies should be individualized on
the basis of the risk of recurrence in the bladder and extravesical
sites (see Table 136.5).
Secondary Prevention Strategies
Lifestyle changes and chemoprevention could potentially reduce the
risk of recurrence and have been considered in the management of
patients with non–muscle-invasive disease.
Lifestyle changes are particularly important because UC is directly
linked to environmental factors in the majority of cases. Smoking
cessation, increased fluid intake, and a low-fat diet may reduce
the risk of recurrence; the former is paramount. Increased hydration
reduces the concentration and dwell time of carcinogens and
thereby reduces the risk of malignant transformation within the
urothelium (Jiang et al., 2008). The Physician Health Study showed
an inverse correlation between fluid intake and the incidence of UC
on longitudinal follow-up, but this simple measure may also be of
benefit for secondary prevention for patients who already have a
history of UC (Michaud et al., 1999). High fat and cholesterol
intake are now firmly established as risk factors for many cancers,
although the mechanisms are not as well defined as for other
malignancies (Steineck et al., 1990).
A variety of agents have been investigated for chemoprevention
strategies for patients with UC, including retinoids (i.e., vitamin A
and its analogues) (Becci et al., 1978; Eichholzer et al., 1996; Sporn
et al., 1977; Steinmaus et al., 2000); pyridoxine (vitamin B6) (Byar
and Blackard, 1977; Newling et al., 1995); α-tocopherol (Lotan
et al., 2005; Virtamo et al., 2000); and difluoromethylornithine
(DFMO) (Messing et al., 2005). However, none of these agents has
proven useful in rigorous trials. Isoflavones were studied for the
same purpose, but the studies were abandoned because of higher
bladder cancer risk in the patients consuming greater amounts of soy
products (Sun et al., 2004). High-dose multivitamins were shown
to decrease the incidence of recurrence especially if administered
along with intravesical BCG therapy (Lamm et al., 1994). However,
a randomized trial conducted subsequently failed to confirm this
initial finding (Nepple et al., 2010).
 Chapter 136  Management Strategies for Non–Muscle-Invasive Bladder Cancer (Ta, T1, and CIS)
KEY POINTS: SURVEILLANCE AND PREVENTION
• Cystoscopy is the hallmark of surveillance. The surveillance
schedule should be individualized on the basis of risk
stratification of the most recently resected tumor.
• Table 136.5 demonstrates reasonable surveillance
protocols based on clinical scenarios.
• A number of tumor markers have shown the ability to
improve the sensitivity of cytology, but specificity is lower
for most.
• Increased fluids, smoking cessation, and a low-fat diet are
recommended.
SUGGESTED READINGS
Chamie K, Litwin MS, Bassett JC, et al; Urologic Diseases in America Project:
Recurrence of high-risk bladder cancer: a population-based analysis, Cancer
119(17):3219–3227, 2013.
3111
Chang SS, Boorjian SA, Chou R, et al: Diagnosis and treatment of non-muscle
invasive bladder cancer: AUA/SUO Guideline, J Urol 196(4):1021–1029,
2016.
Chang SS, Cookson MS: Radical cystectomy for bladder cancer: the case for
early intervention, Urol Clin North Am 32:147–155, 2005.
Chou R, Selph S, Buckley DI, et al: Intravesical therapy for the treatment of
nonmuscle invasive bladder cancer: a systematic review and meta-analysis,
J Urol 197(5):1189–1199, 2017.
Lamm DL, Blumenstein BA, Crissman JD, et al: Maintenance bacillus Calmette-
Guérin immunotherapy for recurrent Ta,T1 and carcinoma in situ TCC of
the bladder: a randomized SWOG study, J Urol 163:1124–1129, 2000.
O’Donnell MA: Practical applications of intravesical chemotherapy and
immunotherapy in high-risk patients with superficial bladder cancer, Urol
Clin North Am 32:121–131, 2005.
Sylvester RJ, Oosterlinck W, van der Meijden AP: A single immediate postopera-
tive 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 171:2186–2190, 2004.
REFERENCES
The complete reference list is available online at ExpertConsult.com.