Ca Bladder

Gejala klinik:

Painless gross hematuria - Approximately 80-90% of patients; classic presentation

Irritative bladder symptoms (eg, dysuria, urgency, frequency of urination) - 20-30% of
patients
Pelvic or bony pain, lower-extremity edema, or flank pain - In patients with advanced
disease
Palpable mass on physical examination - Rare in superficial bladder cancer
Pemeriksaan penunjang
Urinalisis

Mikroskopis
Urinary tumor marker testing (UroVysion (FISH), BTA, and NMP-22 )
Urinary cytology

Standard noninvasive diagnostic method

Low sensitivity for low-grade and early stage cancers
Fluorescence in situ hybridization (FISH) may improve the accuracy of cytology
Cystoscopy

The primary modality for the diagnosis of bladder carcinoma

Permits biopsy and resection of papillary tumors
Upper urinary tract imaging

Necessary for the hematuria workup

American Urologic Association Best Practice Policy CT Scan abdomen dan pelvis
dengan kontras.
Imaging is ideally performed with CT urography, using multidetector CT
Ultrasonography is commonly used, but it may miss urothelial tumors of the upper tract
and small stones

Therapi

Treatment of NonMuscle-Invasive Disease (Ta, T1, CIS)

Immunotherapy and chemotherapy
Intravesical instillation of BCG is used in the treatment of high-risk Ta, T1, and CIS
urothelial carcinoma of the bladder. Immunotherapy with BCG is the most effective
intravesical therapy for CIS and T1 tumors. It is less effective in reducing the 5-year
recurrence rate for low-grade and low-stage urothelial carcinoma (see Table 2, below).
Table 2. Recurrence and Progression Rates at 5 Years for Ta, T1, and CIS TCC of the
Bladder Treated With BCG (Open Table in a new window)
Sta Recurrence Progression
ge , %
,%
Ta

55

11

T1

61

31

CIS

45

23

G1

61

2-4

G2

56

5-7

G3

50-70

30-40

The intravesical instillation of either BCG vaccine or chemotherapy is initiated

approximately 2-4 weeks following endoscopic resection of any visible papillary tumors
or bladder biopsies. By that time, the bladder has usually healed enough to avoid
systemic distribution of the vaccine organism.
See Bacillus Calmette-Gurin Immunotherapy for Bladder Cancer for more information
on this topic.
Interferon alfa or gamma has been used in the treatment of stages Ta and T1 and CIS
urothelial carcinoma, either as single-agent therapy or in combination with BCG. [92] Its
role has primarily been in treatment following BCG failure. Early results in
nonrandomized, retrospective series have reported a 42% response with tolerable
adverse effects after BCG failure. However, no evidence has indicated that retreatment
with BCG with interferon is superior to retreatment with BCG alone.
Patients who have a recurrence within 12 months after 2 courses of BCG (preferably
6+3 treatments) do not benefit from treatment with BCG plus interferon. In addition, in a
randomized study of BCG versus BCG plus interferon in BCG-naive high-risk patients,
the addition of interferon was equivalent to BCG alone. [93]

Kamat et al found that the results of fluorescence in situ hybridization (FISH) assays
can identify patients at risk for tumor recurrence and progression who are undergoing
BCG immunotherapy. This information could be useful in counseling patients about
alternative treatment strategies.[94]
Patients with BCG-refractory CIS may also be treated with intravesical valrubicin
(Valstar), which is currently the only FDA-approved agent for this particular indication.
However, any patient who has persistent or recurrent disease after BCG should be
considered for radical cystectomy, given the high rate of disease progression.
Intravesical docetaxel appears to be a promising agent for BCG-refractory nonmuscleinvasive bladder cancer; adding maintenance treatments of docetaxel may increase the
duration of recurrence-free survival. Barlow et al reported that 32 of 54 patients with
BCG-refractory bladder cancer showed a complete response to 6 weekly treatments of
intravesical docetaxel.[95] Median time to recurrence was 39.3 months in responders
treated with maintenance docetaxel, compared with 19 months in those who did not
receive maintenance therapy.

Surgery
TURBT
Endoscopic TURBT is the first-line means of diagnosing, staging, and treating visible
tumors. Electrocautery or laser fulguration of the bladder tumor is sufficient for lowgrade, small-volume, papillary tumors. However, the 2011 EAU guidelines recommend
resection of small tumors (< 1 cm) in a single piece that includes part of the underlying
bladder wall.
The 2011 EAU and 2012 NCCN guidelines offer similar recommendations for surgical
treatment.[72, 44] Patients with bulky, high-grade, or multifocal tumors should undergo a
second procedure to ensure complete resection and accurate staging 4-6 weeks after
the initial TURBT.
Both guidelines state that a second resection should be performed at this time if these
or other factors, such as an absence of muscle tissue in the initial specimen, indicate
that the initial TURBT was incomplete. Resection of large tumors (>1 cm diameter)
should be performed in fractions, including muscle tissue. [72, 44] Approximately 30% of
stage T1 tumors are upgraded to muscle-invasive disease.
Fluorescence-guided resection
The EAU guidelines recommend fluorescence-guided resection, as it is more sensitive
than white-light cystoscopy alone for detection of tumors, particularly CIS. [96, 97, 98] The
FDA has approved blue-light cystoscopy with hexaminolevulinate (Cysview) as an
adjunct to white-light cystoscopy in patients suspected or known to have nonmuscleinvasive papillary cancer of the bladder on the basis of a prior cystoscopy. This
technique is not a replacement for random bladder biopsies or other procedures used in
the detection of bladder cancer and is not for repetitive use.

Blue-light cystoscopy with hexaminolevulinate detects more Ta/T1 bladder cancer

lesions than does white-light cystoscopy alone. [96, 97, 98, 99, 100] (See the image below.) Stenzl
et al reported that in patients with Ta or T1 tumors, at least one of the tumors was seen
only with fluorescent cystoscopy in 16% of patients. [101]Improved detection leads to
improved tumor resection, as every tumor detected is resected in the same TURBT.[102]

(A) When infused into the bladder, the optical imaging agent
hexaminolevulinate (Cysview) accumulates preferentially in malignant cells. (B) On blue-light cystoscopy,
the collection of hexaminolevulinate within tumors is visible as bright red spots. Courtesy of Gary David
Steinberg, MD, FACS.

No further metastatic workup is needed for obviously superficial tumors. Because

bladder cancer is a polyclonal field change defect, continued surveillance is mandatory.
See Transurethral Resection of Bladder Tumors for more information on this topic.
Radical cystectomy
Although radical cystectomy is typically reserved for muscle-invasive disease, it is also
appropriately used to treat some patients with high-risk, nonmuscle-invasive bladder
cancer, including CIS. Indications in non muscle-invasive disease include the following:
Tumor bulk so substantial that complete eradication of tumor is not feasible
endoscopically

Prostatic urethra involvement

CIS or T1 high-grade tumor persistence despite adequate intravesical

management
Eliminating visible lesions with resection is preferable prior to intravesical BCG, but
some CIS lesions may not be readily visible. Blue-light cystoscopy may improve the
detection of CIS.[101] Patients who do not respond to BCG instillations often find
cystectomy difficult to accept and, instead, want to continue trying various intravesical
instillations.

The difficulty of accurately staging CIS preoperatively was demonstrated by Tilki and a
group of international investigators.[103] These researchers reported that of 243 patients
who were considered to have only CIS before cystectomy, only 117 (48.1%) were found
to actually have CIS; 20 patients (8.2%) had no cancer (pT0), and 19 patients (7.8%)
had urothelial cancer only. The disease was up-staged in 36% of the patients. The
overall 5-year recurrence-free and cancer-specific survival was 74% and 85%,
respectively.
From 35-50% of patients who undergo cystectomy for Ta, T1, or CIS are discovered to
have muscle-invasive disease, with 10-15% demonstrating microscopic lymph node
metastasis. According to the 2012 NCCN guidelines, cystectomy should involve at least
bilateral node dissection, including iliac and obturator nodes. [44]

Patients with T1 high-grade cancer in association with diffuse CIS are at especially high
risk of progression, and they may be treated with early cystectomy based on a decision
made by the physician and patient. The 2011 EAU guidelines recommend that
immediate cystectomy be considered for such patients. [72]
CIS progresses to muscle-invasive disease in upwards of 80% of affected patients, with
20% of patients found to have muscle-invasive disease at the time of cystectomy. Highgrade T1 tumors that recur despite BCG have a 50% likelihood of progressing to
muscle-invasive disease. Cystectomy performed prior to progression yields a 90% 5year survival rate. The 5-year survival rate drops to 30-50% in muscle-invasive disease.
The EAU guidelines strongly advocate cystectomy in patients with early BCG failure.

Treatment of Muscle-Invasive Disease (T2 and Greater)

Radical cystectomy
The criterion standard for the treatment of patients with stage T2-T4 disease is radical
cystoprostatectomy for men and anterior pelvic exenteration for women.
Cystoprostatectomy involves removal of the bladder, peritoneal covering, perivesical fat,
distal ureters, prostate, seminal vesicles, vas deferentia, and, sometimes, the
membranous or entire urethra. Anterior pelvic exenteration consists of cystectomy,
urethrectomy, hysterectomy, salpingo-oophorectomy, and partial anterior vaginectomy.
Both procedures also include regional lymph node dissection.
In experienced hands, robot-assisted radical cystectomy may offer the advantages of
reduced blood loss, opiate requirement, and hospital stay. As this is a relatively new
procedure, surgeons performing it need to provide detailed informed consent and a full
description of potential complications and outcomes. [104]
Emerging retrospective data from multiple institutions suggest that a longer interval from
the time of diagnosis to radical cystectomy can adversely affect pathologic stage and
survival.[105] For example, at the University of Pennsylvania, patients who underwent
radical cystectomy within 12 weeks of the diagnosis had a lower incidence of advanced
pathologic stage (42% vs 84% with extravesical disease), lower incidence of positive
lymph nodes, and an increased 3-year survival rate (62% vs 35% with extravesical
disease).[106]

Pelvic lymphadenectomy
Approximately 25% of patients undergoing radical cystectomy have lymph node
metastases at the time of surgery. Bilateral pelvic lymphadenectomy (PLND) should be
performed in conjunction with radical cystoprostatectomy and anterior pelvic
exenteration. PLND adds prognostic information by appropriately staging the patient
and may confer a therapeutic benefit.

PLND can be performed in a standard or an extended version. The boundaries of a

standard PLND include the bifurcation of the common iliac artery and vein superiorly,
the genitofemoral nerve laterally, the obturator fossa posteriorly, and the circumflex iliac
vein (or node of Cloquet) inferiorly.
Extended PLND includes the lymph nodes in the presacral region and those
surrounding the common iliac vessels to the level of the aortic bifurcation. For a supraextended PLND, dissection can be continued to the level of the inferior mesenteric
artery. Patients with lymph node metastases rarely have skip lesions (ie, positive
nodes in the extended dissection with negative pelvic lymph nodes).
The additional benefit of an extended PLND is controversial. On the basis of several
retrospective studies, some experts believe that an extended dissection provides
additional staging information and offers a survival benefit. However, no randomized
trials to date have proved that an extended PLND is more beneficial than the standard
procedure. A prospective, randomized trial comparing standard with extended pelvic
lymphadenectomy is currently recruiting participants. [107]

Urinary diversion
After cystectomy is performed, a urinary diversion must be created from an intestinal
segment. Diversions can be incontinent or continent. Contraindications to performing
continent urinary diversions are as follows:

Multiple comorbid health problems

Chronic renal insufficiency
Hepatic dysfunction
Advanced disease stage
Incontinent urinary diversion
Conduits can be constructed from either ileum or colon. The most common incontinent
diversion is the ileal conduit (see the image below), which has been used for more than
40 years with excellent reliability and minimal morbidity.

In an ileal conduit, a small segment of ileum is taken out of continuity with

the gastrointestinal tract but is maintained on its mesentery. Ureters are anastomosed to one end of this
ileal segment, and the other end is brought out as a stoma to the abdominal wall.

In this procedure, a small segment of ileum (at least 15 cm proximal to the ileocecal
valve) is taken out of gastrointestinal continuity but maintained on its mesentery, with
care to preserve its blood supply. The gastrointestinal tract is restored with a smallbowel anastomosis. The ureters are anastomosed to an end or side of this intestinal
segment and the other end is brought out as a stoma to the abdominal wall. Urine
continuously collects in an external collection device worn over the stoma.
Continent urinary diversion
The most commonly used continent cutaneous urinary diversion is the Indiana pouch
(see the image below). Introduced in 1987, the Indiana pouch is a urinary reservoir
created from a detubularized right colon and an efferent limb of terminal ileum. The
terminal ileum is plicated and brought to the abdominal wall. The ileocecal valve acts as
a continence mechanism. The Indiana pouch is emptied with a clean, intermittent
catheterization 4-6 times per day.

In an Indiana pouch, a urinary reservoir is created from detubularized

right colon and an efferent limb of terminal ileum. Terminal ileum is plicated and brought to the abdominal
wall. The continence mechanism is the ileocecal valve.

The orthotopic neobladder is another form of continent urinary diversion. In neobladder

diversions (see the image below), various segments of intestine, including the ileum,
ileum and colon, and sigmoid colon, can be used to construct a reservoir. The ureters
are implanted to the reservoir, and the reservoir is anastomosed to the urethra.

In an orthotopic neobladder, a segment of ileum is used to construct a

neobladder, which is connected to the urethra. Orthotopic neobladder most closely restores the natural
storage and voiding function of the native bladder.

Neobladder diversions have been performed successfully in men for more than 20
years and, more recently, in women. The orthotopic neobladder most closely restores

the natural storage and voiding function of the native bladder. Patients have volitional
control of urination and void by Valsalva.
A variety of other continent urinary reservoirs have been developed. These vary
primarily in the continence mechanisms utilized.

Neoadjuvant chemotherapy in muscle-invasive disease

Giving chemotherapy prior to either radical cystectomy or external beam radiotherapy is
controversial. Nevertheless, neoadjuvant chemotherapy prior to radical cystectomy may
improve cancer-specific survival, presumably by treating micrometastatic disease and
pathologic downstaging.[108] A meta-analysis of 11 trials showed an overall survival rate
benefit of 5% in patients who received neoadjuvant chemotherapy.[109]
If locally advanced TCC is suspected, based on clinical staging, the rationale for
neoadjuvant chemotherapy prior to cystectomy may be even stronger. In a multicenter,
randomized, prospective study by the Southwestern Oncology Group (SWOG) of
neoadjuvant therapy with a combination of methotrexate, vinblastine, doxorubicin, and
cisplatin, the investigators concluded that neoadjuvant therapy conferred a treatment
benefit compared with surgery alone for locally advanced bladder cancer.[110]
However, several criticisms of this study exist. The study was underpowered because of
slow recruitment (317 patients over 11 y), because 20% of the patients who were to
undergo cystectomy alone never had the surgery, and because there was no
comparison to neoadjuvant therapy alone or adjuvant therapy. In addition, a study that
reevaluated the SWOG data found that surgical factors significantly affected outcomes.
[111]

Patients with P3-P4 or N+ urothelial carcinoma in the United States are typically advised
to receive adjuvant chemotherapy. In one small series, the T4 tumors of 45% of affected
patients responded to chemotherapy, making potentially curative cystectomy possible.
A phase III trial that assessed 976 patients with muscle-invasive bladder cancer using
neoadjuvant cisplatin, methotrexate, and vinblastine (CMV) chemotherapy found that
risk of death was decreased by 16%.[112] Chemotherapy was followed by cystectomy
and/or radiotherapy. The investigators concluded that neoadjuvant chemotherapy
followed by definitive local therapy should be viewed as a standard of care. At present,
however, perioperative chemotherapy is used in only approximately 33% of cases.