Treatment/Prognosis

Question 1

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

Answer 1

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 2

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

Answer 2

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

Grade 2–3 Dz
T1 lesion
Presence of CIS
Multifocal lesions
Lesions ≥3 cm

Question 3

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

Answer 3

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 4

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

Answer 4

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 5

Is NMIBC likely to recur?

Answer 5

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

Question 6

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

Answer 6

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

Question 7

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

Answer 7

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

RC + LND +/– neoadj or adj chemo

Selective bladder preservation following max TURBT with concurrent CRT

Partial cystectomy + LND +/– neoadj chemo

Question 8

What is involved in an radical cystectomy (RC)?

Answer 8

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 9

What LN regions are typically included in a pelvic LND?

Answer 9

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 10

What are the 3 most common types of urinary diversions?

Answer 10

The 3 most common urinary diversions are:

Continent orthotopic neobladder (e.g., Studer pouch)

Continent cutaneous diversion (e.g., Indiana pouch)

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

Question 11

Estimate the 5-yr OS after RC for MIBC.

Answer 11

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 12

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

Answer 12

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 13

What is the role of adj chemo in MIBC?

Answer 13

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 14

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

Answer 14

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

Question 15

Name 3 predictors of pelvic failure after RC.

Answer 15

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 16

Where are pelvic recurrences after RC typically found?

Answer 16

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 17

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

Answer 17

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 18

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

Answer 18

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 19

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

Answer 19

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:

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

Question 20

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

Answer 20

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 21

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

Answer 21

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 22

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

Answer 22

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 23

Describe the concurrent chemo/RT regimen used in BC2001.

Answer 23

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 24

Describe the chemo and RT used in RTOG 8903.

Answer 24

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 25

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

Answer 25

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 26

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

Answer 26

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

Question 27

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

Answer 27

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 28

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

Answer 28

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 29

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

Answer 29

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 30

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

Answer 30

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

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

Question 31

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

Answer 31

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 32

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

Answer 32

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 33

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

Answer 33

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

Question 34

How is metastatic bladder cancer treated?

Answer 34

Cisplatin-based combination chemo is the preferred initial Tx. GC, or dose-dense 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 35

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

Answer 35

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 36

How is mixed histology or pure nonurothelial bladder cancers treated?

Answer 36

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.