Campbell Bladder Cancer + NCCN Bladder 3.2021 Flashcards
Bladder CA
Risk Factors
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
The gold-standard test for the diagnosis of bladder cancer is: ___
Cystoscopy and biopsy
Blue-light cystoscopy (BLC)
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
Narrow-band imaging (NBI)
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
Inverted papilloma
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
Nephrogenic adenoma
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
Leukoplakia
White, flaky plaques floating in the bladder
NO evidence to suggest that this condition was premalignant; therefore cystoscopy, biopsy, and further treatment were unnecessary.
Cystitis Cystica and Glandularis
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.
Most common malignancy of the urinary tract
Urothelial carcinoma
** Second most common cause of death among all GU tumors
Micropapillary variant
- 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
Sarcomatoid variant
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
Plasmacytoid variant
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;
Nested variant
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
Small Cell
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
Squamous cell cancer
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
Adenocarcinoma
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
Urachal adenocarcinoma
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
Initial evaluation of bladder cancer
• 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
AUA RIsk Stratification for NMIBC
LOW RISK
• Papillary urothelial neoplasm of low malignant potential
• Low grade urothelial carcinoma Ta and
≤3 cm and
Solitary
AUA RIsk Stratification for NMIBC
INTERMEDIATE RISK
• 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
AUA RIsk Stratification for NMIBC
HIGH RISK
• 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
Management NMIBC
LOW RISK
Surveillance
If prior BCG, maintenance BCG (preferred)
Management NMIBC
INTERMEDIATE RISK
Intravesical therapyo,p (preferred)
or
Surveillance
If prior BCG, maintenance BCG (preferred)
Management NMIBC
HIGH RISK
BCG NAIVE
Very-high-risk features
Cystectomy (preferred) or
BCG
Management NMIBC
HIGH RISK
BCG NAIVE
NO Very-high-risk features
BCG (category 1, preferred) or
Cystectomy
Management NMIBC
HIGH RISK
BCG unresponsive or intolerant
Cystectomy (preferred)
or
Intravesical chemotherapy
or
Pembrolizumab (select patients)
POSITIVE URINE CYTOLOGY (negative imaging, negative cystoscopy)
Initial evaluation
• 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
POSITIVE URINE CYTOLOGY
Bladder, prostate, and upper tract negative
Follow-up at 3 mo, then at longer intervals
or o If prior BCG, maintenance BC
POSITIVE URINE CYTOLOGY
Bladder positive
BCG
- NED –> maintenance
- Persistent/recurrent –> cystectomy OR pembrolizumab OR change intravesical agent –> unresponsive, cystectomy OR pembrolizumab
BCG-unresponsive
- Cystectomy OR pembrolizumab
POSITIVE URINE CYTOLOGY
Prostate positive
- 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
POSITIVE URINE CYTOLOGY
Upper tract positive
Initial workup
• 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
UTUC Renal pelvis
Non-metastatic
Low grade
Nephroureterectomy with cuff of bladder ± perioperative intravesical chemotherapye
or f Endoscopic resection
± postsurgical intrapelvic chemotherapy or BCG
UTUC Renal pelvis
Non-metastatic
High grade, large or parenchymal invasion
Nephroureterectomy
with cuff of bladder + regional lymphadenectomy ± perioperative intravesical chemotherapye
and
consider neoadjuvant chemotherapyg in selected patients
UTUC Renal pelvis
Metastatic
Systemic therapy
UTUC Ureter
Initial Workup
• 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
UTUC Ureter
UPPER
Nephroureterectomy with cuff of bladder and regional lymphadenectomy if high grade and consider neoadjuvant chemotherapyg in selected patients
or f
Endoscopic resection
UTUC Ureter
MID
LOW GRADE
Endoscopic resectionf or Nephroureterectomy with cuff of bladder or Excision and ureteroureterostomy/ileal ureter in highly selected patients
UTUC Ureter
MID
HIGH GRADE
Nephroureterectomy with cuff of bladder and regional lymphadenectomy and consider neoadjuvant chemotherapyg in selected patients
UTUC Ureter
DISTAL
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
UTUC Ureter
METASTATIC
Systemic therapy
MUSCLE INVASIVE
St. II
Cystectomy candidate
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)
MUSCLE INVASIVE
St. II
NON-Cystectomy candidate
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
MUSCLE INVASIVE
St. IIIA
cT3, N0; cT4a, N0; cT1–T4a, N1
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
MUSCLE INVASIVE
St. IIIB
(cT1–T4a, N2,3)
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!
MUSCLE INVASIVE St. IVA Stage IVA (cT4b, Any N, M0; Any T, Any N, M1a)
M0:
Systemic therapy
or
Concurrent chemoRT
M1a:
Systemic therapy
MUSCLE INVASIVE
St. IVB
Metastatic
- 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
Radical cystectomy pelvic lymphadenectomy should include:
Common, internal iliac, external iliac, and obturator nodes.
Regional lymphadenectomy for high-grade UT tumors
LEFT-sided renal pelvic, upper ureteral, and midureteral
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.
Regional lymphadenectomy for high-grade UT tumors
RIGHT-sided renal pelvic, upper ureteral, and midureteral tumors:
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.
Regional lymphadenectomy for high-grade UT tumors
DISTAL ureteral tumors
Regional lymphadenectomy should be performed and include the common iliac, external iliac, obturator, and hypogastric lymph nodes.
Immediate post-op intravesical
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
Induction intravesical chemo or BCG
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.
Maintenance intravesical BCG
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.
SYSTEMIC THERAPY Perioperative chemotherapy Preferred regimens and Other regimens
- 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
FIRST LINE FOR METASTATIC
Cisplatin eligible
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
Cisplatin ineligible
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)
Second-line systemic therapy (postplatinum)
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
Second-line systemic therapy (postcheckpoint inhibitor)
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
Radiosensitizing chemotherapy regimens for organ-preserving chemoRT
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
