Campbell Bladder Cancer + NCCN Bladder 3.2021

Question 1

Bladder CA

Risk Factors

Answer 1

Tobacco smoking (MAIN)
Aromatic amines (2-naphthylamine, 4-aminobiphenyl, benzidine)
NAT2 and GSTM1 gene deletions
Lynch syndrome, HNPCC
MSH2 mutations
Increased BMI
Occupational exposure to aromatic amines: tobacco, dye, and rubber workers, hairdressers, painters, and leather workers
Bladder calculi, urinary outflow obstruction, recurrent UTIs, and inflammation from direct catheter trauma
Schistosomiasis (S. hematobium)
Cyclophosphamide
Arsenic in drinking water

Question 2

The gold-standard test for the diagnosis of bladder cancer is: ___

Answer 2

Cystoscopy and biopsy

Question 3

Blue-light cystoscopy (BLC)

Answer 3

360-450 nm
Porphyrin-induced fluorescence cystoscopy uses photoactive porphyrins, such as hexaminolevulinate (HAL), that accumulate preferentially in neoplastic tissue and emit red fluorescence under blue-wavelength light

5-ALA and HAL

Question 4

Narrow-band imaging (NBI)

Answer 4

enhances contrast between mucosal surfaces and microvascular surfaces without the use of dyes.

lluminates the mucosal surface with light of a narrow bandwidth in the blue (415 nm) and green (540 nm) light spectrum, which are strongly absorbed by hemoglobin

Question 5

Inverted papilloma

Answer 5

benign proliferative lesion that is associated with chronic inflammation or bladder outlet obstruction and can be located throughout the bladder but most commonly on the trigone, accounting for less than 1% of all bladder tumors

Painless gross hematuria
Benign behavior, 1% chance of recurrence

Question 6

Nephrogenic adenoma

Answer 6

rare tumor caused by chronic irritation of the urothelium and can arise from trauma, prior surgery, renal transplantation, intravesical chemotherapy, stones, catheters, and infection

Cystoscopy: appear like a papillary neoplasm and may be hard to distinguish from more aggressive bladder neoplasms

Recurrence is uncommon, manageed with repeat resection

Question 7

Leukoplakia

Answer 7

White, flaky plaques floating in the bladder
NO evidence to suggest that this condition was premalignant; therefore cystoscopy, biopsy, and further treatment were unnecessary.

Question 8

Cystitis Cystica and Glandularis

Answer 8

Benign lesions represent cystic nests that are lines by columnar or cuboidal cells and are generally associated with prolifera- tion of Von Brunn nests

Treatment is transurethral resection and relief of the obstruction or inflammatory condition.

Question 9

Most common malignancy of the urinary tract

Answer 9

Urothelial carcinoma

** Second most common cause of death among all GU tumors

Question 10

Micropapillary variant

Answer 10

• ny amount of micropapillary urothelial carcinoma may be present for it to be defined as micropapillary

TX: surgical resection, must be completely resected for TURBT + BCG to be effective;
Early cystectomy for NMIBC

Question 11

Sarcomatoid variant

Answer 11

large infiltrative masses

5-year cancer-specific survival as low as 28.4% across all stages

worse outcomes than pure urothelial tumors

TX: Immediate radical cystectomy when feasible

Question 12

Plasmacytoid variant

Answer 12

rare, comprising less than 1% of all urothelial tumors

includes the signet ring variant: presence of cytoplasmic vacuoles with or without intracellular mucin

metastatic median survival: only 17.7 months

TX: chemosensitive, NAC whenever possible;

Question 13

Nested variant

Answer 13

Rare, aggressive
Male:female ratio 6:1
Can be confused with benign lesions such as Von Brunn nests that are located in the lamina propria, cystitis cystica, and inverted papillomas

Question 14

Small Cell

Answer 14

rare, poorly differentiated neuroendocrine neoplasm
paraneoplastic syndromes associated with small cell carcinoma including hypercalcemia, Cushing syndrome, and sensory neuropathy.

TX: chemosensitive, platinum-based chemotherapy at initial presentation;
Cisplatin + etoposide regimen of choice

Question 15

Squamous cell cancer

Answer 15

S. haematobium or other bacteria, chronic infection
Spinal cord injury + chronic catheterization

Lower incidence of nodal/mets disease, but seen initially at more advanced stages vs urothelial

TX: Adjuvant and intraop radiation = no clear consensus

Question 16

Adenocarcinoma

Answer 16

RFs: bladder exstrophy, schistosomiasis, and chronic irritation or obstruction
Recommended: colonoscopy
No evidence for use of chemo or RT in NAdj or Adj setting
MVAC or GC: little benefit
Other regimen: 5-FU + cisplatin

Question 17

Urachal adenocarcinoma

Answer 17

1/3 of all bladder adenocarcinomas
Allantoic remnant connecting bladder to umbilical cord
Urachal = almost always adenoCA
Criteria:
- Located in the bladder dome or ant. abdominal wall, epicenter at bladder dome
- Could not have widespread cystitis cystica
- Investigae secondary source of adenoCA

Nearly all are muscle invasive

St. I: urachal mucosa
St. II: confined to urachus
St. IIIA: extend locally into bladder IIIB abd. wall IIIC peritoneum
St. IV metastatic

TX: en bloc resection of dome, urachal ligament and umbilicus

Question 18

Initial evaluation of bladder cancer

Answer 18

• H&P
• Office cystoscopy,
enhanced if available
• Consider cytology • Abdominal/pelvic
• Examination under anesthesia (EUA) (bimanual)
     Suspicion of bladder cancer
imagingb that includes imaging of upper urinary tract collecting system before transurethral resection of bladder tumor (TURBT)
• Screen for smoking

Primary evaluation + surgical treatment:

• EUA
• TURBT
• Single dose intravesical chemo within 24 hrs of TURBT: Gemcitabine (pref. cat 1) or mitomycin (cat 1)
• Upper tract imaging if not previously done

Question 19

AUA RIsk Stratification for NMIBC

LOW RISK

Answer 19

• Papillary urothelial neoplasm of low malignant potential
• Low grade urothelial carcinoma Ta and
≤3 cm and
Solitary

Question 20

AUA RIsk Stratification for NMIBC

INTERMEDIATE RISK

Answer 20

• Low grade urothelial carcinoma T1 or
>3 cm or
Multifocal or
Recurrence within 1 year
• High grade urothelial carcinoma Ta and
≤3 cm and
Solitary

Question 21

AUA RIsk Stratification for NMIBC

HIGH RISK

Answer 21

• High grade urothelial carcinoma CIS or
T1 or
>3 cm or
Multifocal
• Very high risk features (any): BCG unresponsivek Variant histologiesl Lymphovascular invasion Prostatic urethral invasion

Question 22

Management NMIBC

LOW RISK

Answer 22

Surveillance

If prior BCG, maintenance BCG (preferred)

Question 23

Management NMIBC

INTERMEDIATE RISK

Answer 23

Intravesical therapyo,p (preferred)
or
Surveillance

If prior BCG, maintenance BCG (preferred)

Question 24

Management NMIBC
HIGH RISK
BCG NAIVE
Very-high-risk features

Answer 24

Cystectomy (preferred) or

BCG

Question 25

Management NMIBC HIGH RISK BCG NAIVE NO Very-high-risk features

Answer 25

BCG (category 1, preferred) or | Cystectomy

Question 26

Management NMIBC HIGH RISK BCG unresponsive or intolerant

Answer 26

Cystectomy (preferred) or Intravesical chemotherapy or Pembrolizumab (select patients)

Question 27

POSITIVE URINE CYTOLOGY (negative imaging, negative cystoscopy) Initial evaluation

Answer 27

``` • If initial positive cytology, consider repeating cytology test within 3 months or • If repeated positive cytology, Consider selected mapping biopsies including transurethral biopsy of prostatec and Cytology of upper tract and Consider ureteroscopy and Consider enhanced cystoscopy if available ```

Question 28

POSITIVE URINE CYTOLOGY | Bladder, prostate, and upper tract negative

Answer 28

Follow-up at 3 mo, then at longer intervals | or o If prior BCG, maintenance BC

Question 29

POSITIVE URINE CYTOLOGY | Bladder positive

Answer 29

BCG - NED --> maintenance - Persistent/recurrent --> cystectomy OR pembrolizumab OR change intravesical agent --> unresponsive, cystectomy OR pembrolizumab BCG-unresponsive - Cystectomy OR pembrolizumab

Question 30

POSITIVE URINE CYTOLOGY | Prostate positive

Answer 30

* Digital rectal examination (DRE) * Cystoscopy (including bladder biopsy) * TUR biopsies of prostate to include stroma * Prostate-specific antigen (PSA) * Needle biopsy if DRE is abnormal (in selected patients) * Imaging of upper tract collecting systema Mucosal prostatic urethra --> TURP and BCG --> if recurrent, surgery Ductal + acini --> surgery! or TURP and BCG --> then recurrent --> surgery! CYSTOPROSTATECTOMY ± URETHRECTOMY (+ neoadjuvant chemo if stromal invasion) Metastatic --> systemic TX

Question 31

POSITIVE URINE CYTOLOGY Upper tract positive Initial workup

Answer 31

``` • Imaging of upper tract collecting systema • Cytology • Cystoscopy • Ureteroscopy and biopsy and/or selective washings • Renal function tests • Chest x-ray or CT • CBC, chemistry profile • Nuclear medicine renal scan (optional) • Bone scana if clinical suspicion or symptoms of bone metastases • Family history; for those at high risk, consider evaluation for Lynch syndrome (<60 y at presentation, personal history of colon ```

Question 32

UTUC Renal pelvis Non-metastatic Low grade

Answer 32

Nephroureterectomy with cuff of bladder ± perioperative intravesical chemotherapye or f Endoscopic resection ± postsurgical intrapelvic chemotherapy or BCG

Question 33

UTUC Renal pelvis Non-metastatic High grade, large or parenchymal invasion

Answer 33

Nephroureterectomy with cuff of bladder + regional lymphadenectomy ± perioperative intravesical chemotherapye and consider neoadjuvant chemotherapyg in selected patients

Question 34

UTUC Renal pelvis | Metastatic

Answer 34

Systemic therapy

Question 35

UTUC Ureter | Initial Workup

Answer 35

``` • Imaging of upper tract collecting systema • Cytology • Cystoscopy • Ureteroscopy and biopsy and/or selective washings • Renal function tests • Nuclear medicine renal scan (optional) • Chest x-ray or CT • CBC, chemistry profile • Bone scana if clinical suspicion or symptoms of bone metastases • Family history; for those at high risk, consider evaluation for Lynch syndrome ```

Question 36

UTUC Ureter | UPPER

Answer 36

Nephroureterectomy with cuff of bladder and regional lymphadenectomy if high grade and consider neoadjuvant chemotherapyg in selected patients or f Endoscopic resection

Question 37

UTUC Ureter MID LOW GRADE

Answer 37

``` Endoscopic resectionf or Nephroureterectomy with cuff of bladder or Excision and ureteroureterostomy/ileal ureter in highly selected patients ```

Question 38

UTUC Ureter MID HIGH GRADE

Answer 38

Nephroureterectomy with cuff of bladder and regional lymphadenectomy and consider neoadjuvant chemotherapyg in selected patients

Question 39

UTUC Ureter | DISTAL

Answer 39

Distal ureterectomy and regional lymphadenectomy if high grade and reimplantation of ureter (preferred if clinically feasible) and consider neoadjuvant chemotherapyg in selected patients or f Endoscopic resection (low grade) or Nephroureterectomy with cuff of bladder and regional lymphadenectomy if high grade and consider neoadjuvant chemotherapyg in selected patients

Question 40

UTUC Ureter | METASTATIC

Answer 40

Systemic therapy

Question 41

MUSCLE INVASIVE St. II Cystectomy candidate

Answer 41

Neoadjuvant cisplatin-based combination chemotherapyw followed by radical cystectomyc (category 1) or Neoadjuvant cisplatin-based combination chemotherapyw followed by partial cystectomyc (highly selected patients with solitary lesion in a suitable location; no Tis) or Cystectomy alone for those not eligible to receive cisplatin-based chemotherapy OR Bladder preservation with concurrent chemoradiotherapyx,y,z (category 1) --> Reasses after 2-3 months --> NO tumor, observe; TUMOR: Tis/Ta/T1: BCG or surgical consolidation or treat as metastatic ``` THEN ADJUVANT TX: Based on pathologic risk, consider Adjuvant cisplatin-based chemotherapyw if no neoadjuvant treatment, or Adjuvant RTy (pT3–4, positive nodes/margins) (category 2B) ```

Question 42

MUSCLE INVASIVE St. II NON-Cystectomy candidate

Answer 42

Concurrent x,y chemoradiotherapy (preferred, category 1) or RT or TURBT THEN: Reassess tumor status 2–3 months after treatment completion ``` TUMOR: Systemic therapyaa or Concurrent chemoradiotherapy or RT alone (if no prior RT)x,y or o TURBT ± intravesical therapy and Best supportive care ``` NO TUMOR: Observe

Question 43

MUSCLE INVASIVE St. IIIA cT3, N0; cT4a, N0; cT1–T4a, N1

Answer 43

Neoadjuvant cisplatin-based combination chemotherapyw followed by radical cystectomyc,bb (category 1) or Cystectomy alone for those not eligible to receive cisplatin-based chemotherapy THEN: OR Bladder preservation with concurrent chemoradiotherapy (category 1) OR Non-cystectomy candidates: • Concurrent chemoRT (preferred Cat 1) OR RT

Question 44

MUSCLE INVASIVE St. IIIB (cT1–T4a, N2,3)

Answer 44

``` Downstaging systemic therapy --> reassess tumor status 2–3 months --> **Complete response: -Consolidation cystectomyc or x,y Consolidation chemoradiotherapy or Observation ** Partial response: -Cystectomyc or Chemoradiotherapy or treat as metastatic **Progression -> treat as metastatic ``` OR ``` Concurrent chemoradiotherapy --> reassess tumor status 2–3 months --> ** Complete response- ffup ** Partial response: If Tis, Ta, or T1, consider intravesical BCGo or Surgical consolidation or treat as metastatic ** Progression: metastatic! ```

Question 45

``` MUSCLE INVASIVE St. IVA Stage IVA (cT4b, Any N, M0; Any T, Any N, M1a) ```

Answer 45

M0: Systemic therapy or Concurrent chemoRT M1a: Systemic therapy

Question 46

MUSCLE INVASIVE St. IVB Metastatic

Answer 46

* Bone scanb if clinical suspicion or symptoms of bone metastases * Chest CT * Consider CNS imaging * Consider biopsy if technically feasible * Estimate GFR to assess eligibility for cisplatin * Molecular/genomic testing THEN: Systemic therapy and/or palliative RT

Question 47

Radical cystectomy pelvic lymphadenectomy should include:

Answer 47

Common, internal iliac, external iliac, and obturator nodes.

Question 48

Regional lymphadenectomy for high-grade UT tumors | LEFT-sided renal pelvic, upper ureteral, and midureteral

Answer 48

Regional lymphadenectomy should include the paraaortic lymph nodes from the renal hilum to the aortic bifurcation. Most midureteral tumors will also include the common iliac, external iliac, obturator, and hypogastric lymph nodes.

Question 49

Regional lymphadenectomy for high-grade UT tumors | RIGHT-sided renal pelvic, upper ureteral, and midureteral tumors:

Answer 49

Regional lymphadenectomy should include the paracaval lymph nodes from the renal hilum to the inferior vena cava (IVC) bifurcation. Most midureteral tumors will also include the common iliac, external iliac, obturator, and hypogastric lymph nodes.

Question 50

Regional lymphadenectomy for high-grade UT tumors | DISTAL ureteral tumors

Answer 50

Regional lymphadenectomy should be performed and include the common iliac, external iliac, obturator, and hypogastric lymph nodes.

Question 51

Immediate post-op intravesical

Answer 51

A single instillation of chemotherapy is administered within 24 hours of surgery (ideally within 6 hours). • Gemcitabine (preferred) (category 1)1 and mitomycin (category 1)2 are the most commonly used agents in the United States for intravesical chemotherapy. Thiotepa does not appear to be effective.3 • Immediate postoperative intravesical chemotherapy reduces the 5-year recurrence rate by approximately 35% and has a number needed to treat to prevent a recurrence of 7. However, it does not reduce the risk of progression or the risk of cancer mortality.3 • It is not effective in patients with an elevated EORTC recurrence risk score (≥5). This includes patients with ≥8 tumors and those with ≥1 recurrence per year. • Contraindications include: bladder perforation, known drug allergy

Question 52

Induction intravesical chemo or BCG

Answer 52

Treatment option for NMIBC. • The most commonly used agents are BCG, mitomycin, and gemcitabine. • In the event of a BCG shortage, BCG should be prioritized for induction of high-risk patients (eg, high-grade T1 and CIS). Preferable alternatives to BCG include mitomycin or gemcitabine. Other options include: sequential gemcitabine/docetaxel, epirubicin, valrubicin, docetaxel, or sequential gemcitabine/mitomycin. If feasible, the dose of BCG may be split (1/3 or 1/2 dose) so that multiple patients may be treated with a single vial in the event of a shortage. • Initiated 3–4 weeks after TURBT with or without maintenance. • Weekly instillations during induction are given for approximately 6 weeks. • Maximum of 2 consecutive cycle inductions without complete response. • Withhold if traumatic catheterization, bacteriuria, persistent gross hematuria, persistent severe local symptoms, or systemic symptoms.

Question 53

Maintenance intravesical BCG

Answer 53

SWOG regimen consisting of a 6-week induction course of BCG followed by maintenance with 3 weekly instillations at months 3, 6, 12, 18, 24, 30, and 36.4 • In the event of a BCG shortage, BCG should be prioritized for high-risk patients (eg, high-grade T1 and CIS), especially in the early maintenance period (ie, 3 and 6 months post-induction). If feasible, the dose of BCG may be split (1/3 or 1/2 dose) so that multiple patients may be treated with a single vial in the event of a shortage. • Ideally maintenance should be given for 1 year for intermediate-risk and 3 years for high-risk NMIBC. • BCG would be withheld if traumatic catheterization, bacteriuria, persistent gross hematuria, persistent severe local symptoms, or systemic symptoms. • Dose reduction is encouraged if there are substantial local symptoms during maintenance therapy.

Question 54

``` SYSTEMIC THERAPY Perioperative chemotherapy Preferred regimens and Other regimens ```

Answer 54

* DDMVAC (dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin) with growth factor support for 3 or 4 cycles * Gemcitabine and cisplatin for 4 cycles Other: • CMV (cisplatin, methotrexate, and vinblastine) for 3 cycles

Question 55

FIRST LINE FOR METASTATIC | Cisplatin eligible

Answer 55

Preferred regimens 4 a,11 • Gemcitabine and cisplatin (category 1) followed by avelumab maintenance therapy (category 1) • DDMVAC with growth factor support (category 1)2,8 followed by avelumab maintenance therapy (category 1

Question 56

Cisplatin ineligible

Answer 56

Preferred regimens 12 a,11 • Gemcitabine and carboplatin followed by avelumab maintenance therapy (category 1) • Atezolizumab13 (only for patients whose tumors express PD-L1b or who are not eligible for any platinum- containing chemotherapy regardless of PD-L1 expression) • Pembrolizumab14 (only for patients whose tumors express PD-L1c or who are not eligible for any platinum- containing chemotherapy regardless of PD-L1 expression) Other recommended regimens • Gemcitabine15 16 • Gemcitabine and paclitaxel Useful under certain circumstances 17 • Ifosfamide, doxorubicin, and gemcitabine (for patients with good kidney function and good PS)

Question 57

Second-line systemic therapy (postplatinum)

Answer 57

``` Preferred regimen 19 • Pembrolizumab (category 1) Other recommended regimens • Paclitaxel24 or docetaxel25 • Gemcitabine15 Alternative preferred regimens • Immune checkpoint inhibitor Nivolumab20 Avelumab21,22 • Erdafitinibf,23 ``` Useful in certain circumstances based on prior medical therapy • Ifosfamide, doxorubicin, and gemcitabine17 • Gemcitabine and paclitaxel16 • Gemcitabine and cisplatin

Question 58

Second-line systemic therapy (postcheckpoint inhibitor)

Answer 58

Preferred regimen for cisplatin ineligible, chemotherapy naïve • Gemcitabine/carboplatin Other: • Erdafitinibf,23 25 • Paclitaxel or docetaxel • Gemcitabine15 Preferred regimens for cisplatin eligible, chemotherapy naïve • Gemcitabine and cisplatin 2 • DDMVAC with growth factor support Useful in certain circumstances based on prior medical therapy • Ifosfamide, doxorubicin, and gemcitabine17 • Gemcitabine and paclitaxel16

Question 59

Radiosensitizing chemotherapy regimens for organ-preserving chemoRT

Answer 59

``` Preferred regimens (doublet chemotherapy is preferred when feasible) • Cisplatini and 5-FU29,30 • Cisplatini and paclitaxel • 5-FU and mitomycin • Cisplatini alone ``` Other recommended regimen • Low-dose gemcitabine