Bladder Cancer

Updated by Brian C. Baumann and John P. Christodouleas

BACKGROUND

How prevalent is bladder cancer in the U.S.?

Bladder cancer is the 4^th most commonly diagnosed cancer in men behind prostate, lung, and colorectal malignancies and the 9^th most commonly diagnosed cancer in women.

How many cases are diagnosed and how many deaths occur annually in the U.S.?

There are ~73,000 cases of bladder cancer and ~15,000 deaths annually.

What are common risk factors for bladder cancer?

Common risk factors include:

1. Smoking

2. Chronic bladder irritation (nephrolithiasis, urinary tract infection, etc.)

3. Chemical exposures (Cytoxan, amino biphenyl, naphthylamine, etc.)

4. Prior pelvic irradiation

5. Schistosoma haematobium infection (associated only with squamous cell carcinoma [SCC])

What is the median age at diagnosis?

The median age is 65 yrs.

Is bladder cancer more common in men or women?

In the U.S., urothelial bladder cancer is diagnosed 3 times more frequently in men than women. For squamous histology, the incidence between men and women are equal.

What is the most common histologic subtype in developed and developing countries?

In developed countries, ~90% of bladder cancers are urothelial carcinomas, formerly called transitional cell carcinomas. In developing countries, SCCs often predominate.

What are the different histopathologic types of bladder cancer in order of decreasing frequency?

The most common histology in the U.S. is urothelial carcinoma (94%) > SCC (3%) > adenocarcinoma (2%) > small cell tumors (1%).

What % of newly detected bladder tumors are Ta/Tis/T1 lesions?

∼70% of bladder cancers are exophytic papillary tumors, with 70% of these confined to the mucosa (Ta/Tis) and 30% confined to the submucosa (T1).

What % of patients have distant metastases at diagnosis?

~8% have metastatic disease at presentation, usually involving bones, lungs, or liver.

WORKUP/STAGING

What is the most common presenting Sx of bladder cancer?

The most common presenting Sx is painless hematuria.

What are the initial steps in the workup of suspected bladder cancer? What additional workup is needed after a cancer diagnosis is established?

1. Perform urine cytology and cystoscopy.

2. If a lesion is identified that is solid, of high grade, or suspicious for muscle invasion, then CT/MRI of the abdomen and pelvis ideally prior to Bx so induced inflammatory changes do not result in overstaging.

3. Perform a transurethral resection of bladder tumor (TURBT) and EUA.

4. If a cancer diagnosis is made, image the upper urinary tract (CT or MRI urography, intravenous pyelogram, renal US, retrograde pyelogram, or ureteroscopy).

5. For muscle-invasive disease, obtain chest imaging (CXR or CT) and consider bone scan if the patient is symptomatic or has an elevated alkaline phosphatase level.

6. Recommended blood work includes CBC/CMP.

For adequate clinical staging, what should be present in the initial TURBT pathologic specimen?

The Bx specimen should contain muscle from the bladder wall to properly stage the tumor.

What are the indications for re-resection after initial TURBT?

Repeat resection should be performed when there is:

1. Incomplete resection of gross tumor

2. High-grade disease and no muscle in specimen

3. Any T1 lesion

What is the AJCC 7^th edition (2011) T-stage criteria for bladder cancer?

Ta: noninvasive papillary carcinoma

Tis: CIS (“flat tumor”)

T1: tumor invades subepithelial connective tissue

T2a: tumor invades superficial muscularis propria (inner half)

T2b: tumor invades deep muscularis propria (outer half)

T3a: microscopic invasion of perivesical tissue

T3b: macroscopic invasion of perivesical tissue

T4a: tumor invades prostatic stroma, uterus, vagina

T4b: tumor invades pelvic wall, abdominal wall

Can a TURBT be used to define the pathologic tumor (pT) stage?

No. pT stage is defined by an evaluation of a cystectomy specimen. TURBT findings are included in the clinical T-stage (cT) staging.

What is the probability of pathologic pelvic nodal involvement based on the pT stage of a bladder tumor?

Pelvic node involvement by pT stage (Stein JP et al., JCO 2001):

Overall: 24% LN+

pT0-T1: 5%

pT2: 18%

pT3 a: 26%

pT3b: 46%

pT4: 42%

Can the cT stage reliably predict occult pathologic pelvic node involvement?

No. cT stage does not reliably predict occult pathologic node involvement because there is significant discordance between cT stage and pT stage. (Goldsmith B et al., IJROBP 2014)

What is the AJCC 7^th edition (2011) N- and M-stage criteria for bladder cancer?

N0: no regional LN involvement

N1: single +LN in true pelvis (hypogastric, obturator, external iliac, or presacral)

N2: multiple LNs in true pelvis

N3: mets to common iliac LN

M0: no distant mets

M1: positive distant mets

Define the AJCC 7^th edition (2011) bladder cancer stage grouping based on TNM status.

Stage 0 a: Ta, N0, M0

Stage 0is: Tis, N0, M0

Stage I: T1, N0, M0

Stage II: T2, N0, M0

Stage III: T3 or T4 a, N0, M0

Stage IV: T4b or N+ or M1

Estimate the 5-yr OS by stage.

5-yr OS rates for bladder cancer based on SEER data:

Stage 0: 98%

Stage I: 88%

Stage II: 63%

Stage III: 46%

Stage IV: 15%

TREATMENT/PROGNOSIS

Which pts with noninvasive bladder cancer can be observed after maximum TURBT?

Observation is indicated for non–muscle invasive bladder cancer pts after max TURBT with all of the following characteristics:

1. Completely resected

2. Ta

3. Grade 1

4. No residual abnormality on urine cytology

What are the indications for adj therapy in pts with non–muscle invasive bladder cancer (NMIBC) treated with TURBT?

Pts with NMIBC should be treated with intravesicular therapies after TURBT if:

1. Grades 2–3

2. T1

3. Tis

4. Multifocal or residual Dz

What agents are commonly used for intravesicular therapy following TURBT for NMIBC?

Intravesicular immunotherapy (bacillus Calmette-Guerin [BCG]) was superior to intravesicular chemotherapy (mitomycin) for preventing tumor recurrence following TURBT for NMIBC based on 4 meta-analyses. Intravesicular therapy is usually initiated 3–4 wks after resection.

Is NMIBC likely to recur?

Yes. Pts with resected non–muscle invasive Dz have a >50% chance of recurrence within 5 yrs.

Which subsets of pts with NMIBC are at highest risk of having a muscle invasive bladder cancer (MIBC) recurrence?

Pts with CIS or high grade T1 NMIBC are at highest risk of developing a MIBC recurrence.

How is a recurrence of NMIBC treated?

Ta or low-grade T1 disease that recurs is treated with repeat TURBT + intravesicular BCG. Recurrent high-grade T1 or CIS disease is treated more aggressively, often with cystectomy. TURBT + concurrent chemo/RT is a noncystectomy option for medically inoperable or selected operable pts with recurrent high-grade T1.

What are the Tx options for pts with node– MIBC (cT2-T4a, N0) who are medically operable?

For medically operable pts with node– MIBC, standard Tx options include:

1. Radical cystectomy (RC) + lymph node dissection (LND) +/– neoadj or adj chemo

2. Selective bladder preservation for pts without high-risk features

3. Partial cystectomy + LND +/– neoadj chemo

What is involved in an RC?

RC removes the bladder, distal ureters, pelvic peritoneum, prostate, seminal vesicles, uterus, fallopian tubes, ovaries, and anterior vaginal wall. Urine can be diverted via a conduit to the abdominal wall or to an orthotopic neobladder.

What regions are typically included in the pelvic LND?

LND typically includes the distal common iliac, internal and external iliac, and obturator nodes but many surgeons advocate an “extended” LND that includes the proximal common iliacs and presacral nodes.

What are the 3 most common types of urinary diversions?

The 3 most common urinary diversions are:

1. Noncontinent diversion with a bowel conduit (e.g., ileal conduit)

2. Continent nonorthotopic catheterizable diversion (e.g., Indiana pouch)

3. Continent orthotopic diversion (e.g., Studer pouch)

Estimate the 5-yr OS after RC for MIBC.

5-yr OS after RC is ∼60% for stage T2 and ∼40% in stages T3-T4a with most patients dying with DM. (Grossman HB et al., NEJM 2003)

Is there evidence to support neoadj chemo prior to RC in MIBC?

Yes. Multiple RCTs suggest a ~5% OS benefit to neoadj chemo + RC compared to RC alone. (Grossman HB et al., NEJM 2003; Sherif A et al., Eur Urol 2004)

What is the argument against standard use of neoadj chemo for MIBC?

Neoadj chemo may represent overtreatment of subsets of pts who actually have pT0-2, pN0 disease. Some favor adj chemo for subsets of MIBC found to have pT3-4 and/or N+ Dz. Small series suggest a benefit of adj chemo after RC, but neoadj and adj chemo paradigms have not been compared.

What % of MIBC pts have pT0 at the time of RC?

~15% of MIBC pts have pT0 at the time of RC. Neoadj chemo improves pT0 rate to ∼38%. (Grossman HB et al., NEJM 2003)

Name 3 predictors of pelvic failure after RC?

The 3 strongest predictors of pelvic failure (isolated and co-synchronous with DM) are pT3-4 disease, +margins, and <10 benign or malignant lymph nodes identified in the LND specimen. (Baumann BC et al., ASTRO 2013)

Where are pelvic recurrences after RC typically found?

In pT3-4 patients with –margins, failures occur predominantly along the pelvic sidewalls (obturator and iliac regions). In pT3-4 patients with +margins, most pelvic failures are still found along the sidewalls, but recurrences in the cystectomy bed and presacral region increase significantly. (Baumann BC et al., IJROBP 2013)

Is there a role for postop RT (PORT) in MIBC pts with +margins?

Yes. PORT is commonly offered to MIBC pts with +margins because 5-yr the pelvic recurrence rate is ∼68% and long-term survival after isolated pelvic recurrence is <5%. (Herr HW et al., JCO 2004)

Is there a role for PORT in MIBC pts with –margins?

Possibly. There are no RCTs comparing PORT to observation specifically in margin– pts. However, the RCT by Zaghloul M et al. randomized pts with locally advanced MIBC with or without +margins to observation, hyper-fx PORT, or standard fx PORT. (IJROBP 1992) PORT significantly improved the 5-yr disease-free survival (DFS) in the hyper-fx and standard fx PORT arms (49% and 44%, respectively) compared with the observation arm (25%). Most pts in this trial had SCC. The value of PORT for urothelial MIBC treated with modern surgery and chemotherapy is being studied.

Is there a role for preop RT?

Possibly. Preop RT was commonly used in the past but abandoned when several small RCTs performed in the 1970s and 1980s showed no survival benefit. These trials had limited power and included early-stage pts unlikely to benefit. (Huncharek M et al., Anticancer Res 1998) A small RCT of SCC and urothelial cancer pts compared preop RT vs. PORT and found similar efficacy and toxicity. (El-Monin HA et al., Urol Oncol 2013)

What factors are used to select MIBC pts for selective bladder preservation?

Ideal candidates for selective bladder preservation have:

1. Good baseline bladder function

2. Unifocal, cT2-3 tumors

3. Limited CIS

4. No hydronephrosis

5. A visibly complete TURBT

Only 6%–19% of medically operable MIBC pts are good candidates for selective bladder preservation. (Sweeney P et al., Urol Clin N Am 1992)

What is the difference between continuous-course and split-course selective bladder preservation paradigms?

The continuous course paradigm completes the entire course of planned chemo/RT and assesses response with TURBT ∼3 mos after. The split-course paradigm involves an induction chemo/RT phase, a planned break with response assessment ∼3 wks after, and a consolidation chemo/RT phase.

Is there evidence that concurrent chemo-RT is superior to RT alone in MIBC?

Yes. The BC2001 randomized MIBC to concurrent chemo/RT vs. RT alone. 2-yr local-regional DFS favored chemo/RT (67% vs. 54%). (James ND et al., NEJM 2012)

Is there a role for neoadj chemotherapy prior to chemo-RT for bladder preservation?

RTOG 8903 randomized MIBC pts to neoadj methotrexate/cisplatin/vinblastine (MCV) + cisplatin/RT vs. cisplatin/RT alone. Neoadj MCV did not improve pCR, DM, or OS and was poorly tolerated, with only 67% of patients completing the prescribed therapy. (Shipley WU et al., JCO 1998)

Describe the concurrent chemo and RT regimen used in BC2001.

In the concurrent chemo/RT arm of BC2001, MIBC pts were treated with 5-FU + mitomycin and 64 Gy/32 fx qd or 55 Gy/20 fx qd. The trial included a 2^nd randomization to either standard whole bladder RT (PTV: noninvolved bladder + 1.5-cm margin + 2-cm margin around any extravesicular Dz) or to reduced high-dose volume RT, where dose to uninvolved bladder was 80% of max. Pelvic nodes were not intentionally targeted. (James ND et al., NEJM 2012)

Describe the chemo and RT used in RTOG 8903.

In the concurrent chemo/RT alone arm of RTOG 8903, MIBC pts were treated with induction cisplatin q3 wks + 39.6 Gy/22 fx qd targeting the small pelvis (whole bladder, perivesicular, obturator, external iliac and internal iliac nodes). Complete responders were treated with consolidation cisplatin q3 wks + 5.4 Gy/3 fx to the small pelvis followed by a boost to the tumor bed of 19.8 Gy/11 fx (total 64.8 Gy). (Shipley WU et al., JCO 1998)

How are locally recurrent NMIBC and MIBC treated after bladder preservation?

Recurrent NMIBC may be treated with TURBT + intravesicular therapy. Recurrent MIBC is treated with prompt RC.

Estimate the CR rate at initial assessment and 5-yr OS after selective bladder preservation.

60%–80% of pts have a CR at initial post-Tx TUBRT after selective bladder preservation. 5-yr OS 40%–60%. OS after selective bladder preservation appears comparable to OS after RC, but the 2 Txs have not been compared in an RCT.

What are the Tx options for pts with node– MIBC (cT2-T4 a, N0) who are medically inoperable?

For medically inoperable pts with node– MIBC, the most well-established option is definitive chemo/RT. Pts unfit for definitive chemo/RT should have maximal safe TURBT and can be offered observation, RT alone, or chemo alone.

How does the chemo-RT technique differ for medically operable and inoperable pts?

For medically inoperable pts, only continuous-course paradigm is used, since salvage RC is not an option. Similar doses and target volumes are used, though there is a stronger case for pelvic nodal radiation in inoperable pts because they often have more advanced disease and there is no concern about complicating the urinary diversion of a salvage RC.

What are the Tx options for locally advanced bladder tumors (e.g., cT4b or cN+)?

For cT4b or cN+ bladder cancers, Tx options are:

1. Definitive chemo/RT → cystectomy (if possible) or adj chemo

2. Induction chemo → cystectomy (if possible) or definitive chemo/RT or additional chemo

Estimate the 5-yr OS for medically inoperable or locally advanced MIBC treated with definitive chemo-RT.

SWOG 9312 was a single arm trial including 53 pts with cT2-4, any N, who were medically inoperable, unresectable, or refused surgery. Tx included max TURBT → cisplatin/5-FU + 60 Gy → adj cisplatin/5-FU. 5-yr OS ∼32%.

What are the 1^st-line chemo regimens for bladder cancer?

Gemcitabine + cisplatin (GC) or dose-dense MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) are considered 1^st-line chemo regimens for neoadj, adj, or palliative chemo (per NCCN 2014).

How is metastatic bladder cancer treated?

Cisplatin-based combination chemo is the preferred initial Tx. GC, or dose-dense MVAC are frequently used. GC is often preferred over MVAC because of similar efficacy and reduced toxicity. (von der Maase H et al., JCO 2000) For patients with impaired renal function or ECOG performance status ≥2, carboplatin-based chemo is often used. Local therapy (surgery or RT) may be considered depending on the extent of response to palliative chemo.

How is mixed histology or pure nonurothelial bladder cancers treated?

Tumors of mixed histology with urothelial elements generally have a poorer prognosis but should be treated like pure urothelial carcinoma. Tumors with a small cell component are treated with neoadj chemo using small-cell regimens followed by RC or RT. Tx of SCC or adenocarcinoma uses chemo specific to the lesion’s histology.

TOXICITY

What are the operative mortality rates and perioperative complication rates following radical cystectomy?

Operative mortality rates are 2%–5% with short-term complication rates of 28%–57%. In a randomized trial of open vs. robotic cystectomy, short-term grade ≥3 morbidity was 22%–24% with no difference in morbidity between the 2 techniques. (Laudone VP et al., AUA 2013 abstract)

What are the toxicities associated with RT for organ preservation?

Short-term complications: transient urinary frequency/urgency, dysuria, hematuria, bladder spasms, diarrhea, radiation dermatitis, fatigue

Relatively common long-term complications: chronic urinary frequency/urgency, erectile dysfunction, diarrhea

Uncommon long-term complications: chronic hematuria, dysuria, hematochezia, bowel obstructions or fistulas, 2^nd cancers or fractures in the irradiated field

What is the impact of organ preservation approaches on QOL for patients with bladder cancer?

QOL for patients after bladder preservation therapy is good. Urodynamic studies and patient-reported outcomes from the Massachusetts General Hospital found that 78% of patients retained normal bladder function with 85% reporting little-to-no urinary urgency. Bowel symptoms were reported by 22%. 50% reported normal erectile function. (Zietman ZS et al., J Urol 2003)

How many patients require cystectomy for palliation of Tx-related toxicities following bladder preservation?

Cystectomies performed for palliation of bladder preservation–related toxicities are very uncommon with rates of 0%–2%. (Rodel C et al., JCO 2002; Shipley WU et al., J Urol 2002)

What is the recommended follow-up for patients with MIBC treated with bladder preservation?

Urine cytology, cystoscopy + Bx, imaging of the upper urinary tracts, abdomen, pelvis q3–6 mos for the first 2 yrs, and then at increasing intervals. LFTs, BMP, and chest imaging performed q6–12 mos.

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