Bladder cancer

Question 1

How prevalent is bladder cancer in the United States?

Answer 1

Bladder cancer is the 4th most commonly diagnosed cancer in men behind prostate, lung, and colorectal malignancies, but it is only the 11th most common cancer in women.

Question 2

How many cases are diagnosed and how many deaths occur annually in the United States?

Answer 2

There are ∼77,000 cases of bladder cancer and ∼16,000 deaths annually

Question 3

What are common risk factors for bladder cancer?

Answer 3

1. Smoking
2. Occupational chemical exposures (paint, dye, metal, and petroleum products)
3. Chronic bladder irritation (Chronic cystitis, indwelling catheters, etc.)
4. Prior pelvic irradiation or chemo (cyclophosphamide)
5. Schistosoma haematobium infection (associated only with SCC)

Question 4

What is the median age at Dx?

Answer 4

The median age is 69 yrs in men and 71 yrs in women.

Question 5

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

Answer 5

In developed countries, ∼90% of bladder cancers are urothelial carcinomas, formerly called transitional cell carcinomas. In countries where schistosomiasis is endemic, SCC is more common.

Question 6

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

Answer 6

The most common histology in the United States is urothelial carcinoma (94%) > SCC (3%) > adenocarcinoma (2%) > neuroendocrine tumors (1%).

Question 7

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

Answer 7

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

Question 8

What % of pts have DMs at Dx?

Answer 8

∼4% have metastatic Dz at presentation, usually involving bones, lungs, or liver.

Question 9

What is the most common presenting Sx of bladder cancer?

Answer 9

The most common presenting Sx is painless hematuria.

Question 10

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

Answer 10

1. Perform cystoscopy and urine cytology.
2. If a lesion is identified that is solid or suspicious for muscle invasion, then obtain a CT/MRI of the abdomen and pelvis, ideally prior to Bx so induced inflammatory changes do not result in overstaging.
3. Perform an EUA and TURBT.
4. If a cancer Dx is made, image the upper urinary tract (CT or MRI urography, intravenous pyelogram, renal US, retrograde pyelogram, or ureteroscopy).
5. For muscle-invasive Dz, obtain chest imaging (CXR or CT) and consider a bone scan if the pt is symptomatic or has an elevated alk phos level.
6. Recommended blood work includes CBC/CMP.

Question 11

For adequate clinical staging, what should be present in the initial transurethral resection of bladder tumor (TURBT) pathologic specimen?

Answer 11

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

Question 12

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

Answer 12

Repeat resection should be performed when there is:

1. Incomplete resection of gross tumor
2. High-grade Dz and no muscle in specimen
3. Any T1 lesion

Question 13

What are the AJCC 8th edition (2017) T-stage criteria for bladder cancer?

Answer 13

Ta: noninvasive papillary carcinoma
Tis: CIS (“flat tumor”)
T1: tumor invades lamina propria (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 directly into prostatic stroma, seminal vesicles, uterus,
vagina
T4b: tumor invades pelvic wall, abdominal wall

Question 14

Can a TURBT be used to define the pT stage?

Answer 14

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

Question 15

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

Answer 15

Pelvic node involvement by pT stage (Stein JP et al., JCO 2001):
Overall: 24% LN+
pT0–T1: 5%
pT2: 18%
pT3a: 26%
pT3b: 46%
pT4: 42%

Question 16

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

Answer 16

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

Question 17

What are the AJCC 8th edition (2017) N- and M-stage criteria for bladder cancer?

Answer 17

N0: no regional LN involvement
N1: single +LN in true pelvis (perivesical, obturator, internal and external
iliac, or sacral)
N2: multiple regional LNs in true pelvis
N3: mets to common iliac LN
M0: no DMs
M1: DMs
M1a: DMs limited to LNs beyond the common iliacs
M1b: non-LN DMs

Question 18

Define the AJCC 8th edition (2017) bladder cancer stage grouping based on TNM status

Answer 18

Stage 0a: Ta, N0, M0
Stage 0is: Tis, N0, M0
Stage I: T1, N0, M0
Stage II: T2a/T2b, N0, M0
Stage IIIA: T3a/T3b/T4a, N0, M0 or T1–T4a, N1, M0
Stage IIIB: T1–T4a, N2/N3, M0
Stage IVA: T4b, Any N, M0 or Any T, Any N, M1a
Stage IVB: Any T, Any N, M1b

Question 19

Estimate the 5-yr OS for bladder cancer by stage.

Answer 19

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%

Question 20

Which pts with non-muscle invasive bladder cancer (NMIBC) can be observed after max TURBT?

Answer 20

Observation is indicated for NMIBC pts after max TURBT with all of the following characteristics:

1. Solitary, low-grade Ta tumor
2. Completely resected
3. <3 cm in diameter
4. No evidence of CIS

Question 21

What are the indications for adj therapy in NMIBC treated with TURBT?

Answer 21

Pts with NMIBC should be treated with intravesical therapy after TURBT if:

1. Grade 2–3 Dz
2. T1 lesion
3. Presence of CIS
4. Multifocal lesions
5. Lesions ≥3 cm

Question 22

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

Answer 22

Intravesical immunotherapy with Bacillus Calmette-Guerin (BCG) is the Tx of choice for high-risk pts. Alternatives include intravesical chemo such
as mitomycin C, epirubicin, and gemcitabine. BCG decreases the risk of progression and recurrence compared to chemo.

Question 23

Is there a role for RT in the management of NMIBC?

Answer 23

Possibly. RT is occasionally used for high-grade T1 Dz. A retrospective review of 141 pts with high-risk T1 Dz, intravesical therapy naïve, who rcvd either RT or chemoRT, found a complete cystoscopic response in 88% of pts and tumor progression in 19% and 30% of pts at 5 and 10 yrs, respectively (Weiss C et al., JCO 2006). The ongoing RTOG 0926 is evaluating the efficacy of bladder preservation therapy in high-grade T1 pts who have failed intravesical BCG and are candidates for cystectomy.

Question 24

Is NMIBC likely to recur?

Answer 24

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

Question 25

Which subsets of NMIBC pts are at highest risk of having an muscleinvasive bladder cancer (MIBC) recurrence?

Answer 25

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

Question 26

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

Answer 26

For medically operable pts with node(-) MIBC, standard Tx options include:

1. RC + LND +/– neoadj or adj chemo
2. Selective bladder preservation following max TURBT with concurrent CRT
3. Partial cystectomy + LND +/– neoadj chemo

Question 27

What is involved in an radical cystectomy (RC)?

Answer 27

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

Question 28

What LN regions are typically included in a pelvic LND?

Answer 28

A standard pelvic LND includes the distal common iliac, internal and external iliac, and obturator nodes. Evidence suggests that an “extended” LND which includes the proximal common iliacs and presacral nodes may result in sup RFS. The value of extended LND is the subject of 2 ongoing RCTs.

Question 29

What are the 3 most common types of urinary diversions?

Answer 29

The 3 most common urinary diversions are:

1. Continent orthotopic neobladder (e.g., Studer pouch)
2. Continent cutaneous diversion (e.g., Indiana pouch)
3. Noncontinent diversion with a bowel conduit (e.g., ileal conduit)

Question 30

Estimate the 5-yr OS after RC for MIBC.

Answer 30

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

Question 31

What is the evidence to support neoadj chemo prior to RC in MIBC?

Answer 31

Neoadj chemo is considered the standard of care for pts with MIBC. A 2003 meta-analysis of 11 RCTs demonstrated a 5% OS benefit with neoadj
cisplatin-based chemo + RC compared to RC alone. (Lancet 2003)

Question 32

What is the role of adj chemo in MIBC?

Answer 32

There is a paucity of high-level evidence regarding the role of adj chemo in MIBC. For pts who did not rcv neoadj chemo prior to RC, adj chemo may be
offered for those with pT3–4 and/or N+ Dz. Observational series suggest a benefit of adj chemo after RC compare to observation alone.

Question 33

What % of MIBC pts are found to be pT0 at the time of RC without neoadj chemo?

Answer 33

∼15%. Neoadj chemo improves pT0 rate to ∼38%. (Grossman HB et al., NEJM 2003)

Question 34

Name 3 predictors of pelvic failure after RC.

Answer 34

The 3 strongest predictors of pelvic failure (isolated and co-synchronous with DM) are pT3–4 Dz, +margins, and <10 benign or malignant LNs identified in the LND specimen. (Christodouleas JP et al., Cancer 2014)

Question 35

Where are pelvic recurrences after RC typically found?

Answer 35

In pT3–4 pts with –margins, failures occur predominantly along the pelvic sidewalls (obturator and iliac regions). In pT3–4 pts 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)

Question 36

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

Answer 36

Possibly. NCCN guidelines recommend considering adj RT for +margins following RC as the 5-yr pelvic recurrence rate is ∼68% and long-term survival after isolated pelvic recurrence is poor (<5%) (Herr HW et al., JCO 2004). There is, however, no randomized evidence supporting the role of adj RT in this subset of pts.

Question 37

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

Answer 37

Possibly. An Egyptian RCT by Zaghloul et al., randomized pts with locally advanced MIBC with –margins to adj RT alone (45 Gy in 1.5 Gy/fx BID),
sequential chemo (2 cycles gem/cis before and after RT) plus RT, or chemo alone (4 cycles gem/cis). LRFS was significantly improved in the RT arms compared to chemo alone (87% and 96% vs. 69%). There was no significant difference in DFS or OS, although there was a trend toward improved DFS in the RT-containing arms (63% and 68% vs. 56%). (Zaghloul MS, et al., ASCO GU 2016 Abstract)

Question 38

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

Answer 38

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

1. Good baseline bladder function
2. Unifocal, cT2–3 tumors
3. Limited to no CIS
4. No hydronephrosis
5. A visibly complete TURBT

Question 39

What is the difference b/t continuous-course and split-course selective bladder preservation paradigms?

Answer 39

The continuous-course paradigm completes the entire course of planned chemo/RT and assesses response with TURBT ∼3 mos later. The split-course
paradigm involves an induction chemo/RT phase, a planned break with response assessment ∼3 wks later, and a consolidation chemo/RT phase if there is a good response to the initial phase; otherwise salvage RC is
recommended.

Question 40

Is there evidence that concurrent chemoRT is sup to RT alone in MIBC?

Answer 40

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

Question 41

Is there a role for neoadj chemo prior to chemoRT for bladder preservation?

Answer 41

Possibly. RTOG 8903 randomized MIBC pts to neoadj
Mtx/cisplatin/vinblastine (MCV) + cisplatin/RT vs. cisplatin/RT alone, but closed prematurely d/t a high rate of severe neutropenia (Shipley WU et al., JCO 1998). A larger RCT by an international collaboration randomized RT and radical cystectomy pts to neoadj MCV and found an ∼5% advantage to chemo group which did not vary by type of local therapy. (International Collaboration of Trialists 1999)

Question 42

Describe the concurrent chemo/RT regimen used in BC2001.

Answer 42

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 2nd 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)

Question 43

Describe the chemo and RT used in RTOG 8903.

Answer 43

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 f/b a boost to the tumor bed of 19.8 Gy/11 fx (total 64.8 Gy). (Shipley WU et al., JCO 1998)

Question 44

Should clinically uninvolved pelvic LNs be targeted with RT with the bladder preservation approach?

Answer 44

Unclear. Large series have reported that pelvic nodal failure rates with muscle-invasive bladder are relatively high (25%–40%) following cystectomy. In BC2001, however, pelvic nodes were not targeted with RT
and the pelvic nodal failure rates were low in both arms—4.9% in the chemoRT arm and 6.7% in the RT alone arm (James ND et al., NEJM 2012).There is practice variation regarding whether pelvic nodes are electively
targeted.

Question 45

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

Answer 45

Recurrent NMIBC may be treated with TURBT + intravesical therapy.
Recurrent MIBC is treated with salvage RC.

Question 46

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

Answer 46

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

Question 47

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

Answer 47

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

Question 48

How does the chemoRT technique differ for medically operable and inoperable pts?

Answer 48

For medically inoperable pts, the continuous-course paradigm is used, since salvage RC is not an option. The RT doses and target volumes are similar, though there is a stronger case for pelvic nodal RT in inoperable pts b/c they often have more advanced Dz, and there is no concern about complicating the urinary diversion of a salvage RC.

Question 49

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

Answer 49

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

1. Concurrent chemo/RT → cystectomy (if good response) or adj chemo
2. Chemo → chemo/RT or cystectomy (if good response) or further systemic therapy

Question 50

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

Answer 50

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

Question 51

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

Answer 51

Gemcitabine + cisplatin (GC) or dose-dense MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) are considered 1st-line chemo regimens for neoadj, adj, or palliative chemo. (NCCN 2018)

Question 52

What sensitizing chemo regimens are used for concurrent Tx with RT?

Answer 52

Commonly used regimens are mitocycin and 5-FU, BCON, cisplatin and 5-FU, cisplatin and paclitaxel, cisplatin alone and gemcitabine alone.

Question 53

How is metastatic bladder cancer treated?

Answer 53

Cisplatin-based combination chemo is the preferred initial Tx. GC, or dosedense MVAC are frequently used. GC is generally preferred over MVAC as it has similar efficacy with reduced toxicity (von der Maase H et al., JCO 2000). For pts with impaired renal function or ECOG PS ≥2, PD1/L1 inhibitor may be used.

Question 54

What is the role of immunotherapy in the Tx of metastatic bladder cancer?

Answer 54

Immunotherapy has emerged as the preferred 2nd-line Tx for metastatic Dz after progression on 1st-line platinum-based chemo. In the phase III Keynote-
045 trial, pembrolizumab improved OS and DFS compared to chemo in the 2nd-line metastatic setting (Bellmunt et al., NEJM 2017). Atezolizumab, nivolumab, durvalumab, and avelumab have also been approved for 2nd-line Tx of metastatic urothelial cancer. Based on Phase II data, Atezolizumab has been approved as initial therapy for metastatic Dz in pts who are not candidates for cisplatin-based chemo.

Question 55

How is mixed histology or pure nonurothelial bladder cancers treated?

Answer 55

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 or neuroendocrine component are treated with neoadj chemo f/b RC or RT. Tx of SCC or adenocarcinoma uses chemo specific to the lesion’s
histology.

Question 56

What are the toxicities associated with RT for organ preservation?

Answer 56

Short-term complications: transient urinary frequency/urgency, dysuria, hematuria, bladder spasms, diarrhea, RT dermatitis, fatigue
Relatively common long-term complications: chronic urinary frequency/urgency, erectile dysfunction, diarrhea
Uncommon long-term complications: chronic hematuria (especially in pts on blood thinners), dysuria, urgency, bowel obstructions or fistulas, pelvic insufficiency fractures, 2nd cancers

Question 57

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

Answer 57

QOL for pts after bladder preservation therapy is good. Urodynamic studies and pt-reported outcome studies found that 78% of pts retained normal bladder function; bowel Sx were reported by 22% and 50% reported normal erectile function (Zietman ZS et al., J Urol 2003). A recent QOL study compared MIBC pts receiving cystectomy vs. organ preservation trimodality
therapy. At 5.6-yr median follow-up, multivariate analysis showed that the organ preservation group a better general QOL as well as better bowel function, fewer bowel Sx, and better sexual function compared to the
cystectomy group; urinary Sx scores were similar. (Mak KS et al., IJROBP 2016)

Question 58

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

Answer 58

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

Question 59

What is the recommended f/u for pts with MIBC treated with bladder preservation?

Answer 59

Urine cytology, cystoscopy + Bx, imaging of the upper urinary tracts, abdomen, pelvis q3–6 mos for the 1st 2 yrs, and then at increasing intervals.
LFTs, BMP, and chest imaging performed q6–12 mos.