Campbell Management Strategies for NMIBC Flashcards
Low-grade Ta lesions recurrence rate ____ and progression rate ____.
Ta Recurrence rate 50-70% and Progression rate less than 5% of cases
High-grade T1 lesions recurrence rate ____ and progression rate ____ .
High-grade T1 recurrence rate 80%
Progression rate 50% in 3 years
Prognosis correlates with: (5)
Tumor size Multiplicity Papillary vs sessile configuration Presence or absence of LVI Status of remaining epithelium
High grade and low grade CAs may essentially be considered ___.
Different diseases
Chromosomal alterations –> oxidative DNA damage –> 2 separate genetic pathways in UC development
____ tumors could almost be considered benign in contrast to ___ tumors.
Papillary Ta tumors = almost considered benign compared to high-grade tumors.
____ of Ta tumors are high grade.
Most important risk factor for progression is ___, NOT ____
2.9% to 18% are high grade.
Most important risk factor for progression is GRADE, NOT stage.
CIS is regarded as a precursor to the development of ____.
Invasive high-grade cancer
Lesions interpreted as ____ are regarded as being the same entity as CIS.
Severe/high-grade dysplasia
____ % of patients with CIS develop muscle invasion if untreated, especially if associated with papillary tumors.
40-83% of CIS develop MIBC, esp. if associated with papillary tumors.
T1 tumors = usually papillary with a narrow stalk.
A ___ appearance suggests deeper invasion.
Nodular or sessile appearance
Deep penetration into the ____ increases the risk of ___ and ___.
Lamina propria, muscularis mucosae
Increases risk of recurrence and progression
These also increase risk of progression and recurrence in T1 tumors: (3)
LVI
Pyuria
Bladder neck involvement
____ often indicated muscle invasion.
Hydronephrosis
CT urography is commonly performed BEFORE TUR to: (2)
Identify other sources of hematuria
Assess extravesical urothelium (field change nature of UC)
Resection is performed using ____ irrigation and resectoscope, with bladder filled _____.
This minimizes: (3)
Continuous flow
Only enough to visualize bladder contents
(3)
Bladder wall movement
Lessens thinning of detrusor due to overdistention
Reduces risk of perforation
____ tumors can be removed without the use of electrical energy.
___ lessens the chance of perforation.
Friable, low-grade tumors
Lifting the tumor edge away from detrusor
** minimizes chances of bladder perforation and unnecessary cautery damage
After visible tumor is resected, an additional pass of the cutting loop or cold-cup biopsy can be obtained to ____.
…determine the presence of muscle invasion.
Non-muscle invasive bladder CA is the term for malignant urothelial tumors that ___.
… have NOT invaded the detrusor muscle of the bladder.
** Encompasses the relatively benign course of low-grade papillary tumors, the more aggressive clinical course of high-grade tumors including urothelial carcinoma in situ (CIS), and high-grade Ta and T1 tumors
Approximately ____ of bladder tumors are non–muscle invasive at presentation with:
____ as stage Ta
____ as T1, and approximately
____ as CIS
Approximately 70% to 80% of bladder tumors are non–muscle invasive at presentation with 60% to 70% as stage Ta, 20% to 30% as T1, and approximately 10% as CIS
____ is the most common presenting symptom of NMIBC.
The presence of ____ in the absence of ____ is also associated with CIS with some studies reporting rates of up to ___ %.
Painless hematuria (either visible or non-visible).
** Patients with visible hematuria have reported rates of bladder cancer much higher than that observed in patients with non-visible (>3 RBC/hpf on microscopic urinalysis) hematuria.
The presence of irritative voiding symptoms in the absence of UTI; up to 80%
____ and ____ are indicated in patients with hematuria and/or unexplained irritative symptoms.
Cystoscopy and upper tract imaging are indicated in patients with hematuria and/or unexplained irritative symptoms.
** In a review of 600 patients diagnosed with interstitial cystitis, 1% of the patients had a missed diagnosis of urothelial carcinoma, although the majority of these patients did not have hematuria.
Resection of diverticular tumors presents significant risk for ___.
Accurate staging is difficult because of ____.
Therefore: low grade diverticular tumors are best treated with ____ + ____ , followed by ____ if high-grade.
Bladder wall perforation
The absence of underlying detrusor.
**Invasion beyond the diverticular lamina propria immediately involves perivesical fat (stage T3a by definition)
Combined resection + fulguration of the base
Followed by repeat resection if high-grade
** High-grade requires adequeate sampling of tumor base despite near certainty of perforation –> leave IFC for several days to allow for urothelial healing.
Partial or radical cystectomy should be strongly considered for high-grade diverticular lesions because _____.
…tumors can penetrate extravesically with relative ease given the lack of a muscularis layer in the diverticula
Tumor near the ureteral orifice:
____ causes minimal scarring and may be safely performed, including resection of the orifice if necessary.
Pure cutting current
*** Resection of the intramural ureter may lead to complete eradication of some tumors but risks reflux of malignant cells. The clinical implications of this are unclear
** As long as resection of the ureteral orifice is performed with pure cutting current, scarring is minimal and obstruction unlikely.
____ resection of bladder tumors represents another alternative, relatively novel resection technique that can be performed with the traditional loop electrode, Hybrid-Knife, holmium laser, Thulium laser, or KTP lase.
En bloc
***This technique involves excision of the entire tumor with underlying segment of muscle with the specimen being resected and extracted intact, rather than piecemeal. The benefit of this derives from less cautery artifact, thereby allowing more accurate assessment of muscle invasion by pathology.
If a tumor appears to be muscle invasive, may be performed in lieu of complete resection, given the likelihood of subsequent cystectomy.
Biopsies of the borders and base to establish invasion
TURBT: Perforations tend to occur in ___ with ___, particularly in cases involving previous treatment with multiple courses of intravesical therapy
Perforations tend to occur in elderly patients with large posterior wall tumors, particularly in cases involving previous treatment with multiple courses of intravesical therapy.
The incidence of perforation can be reduced by attention to technical details (3):
- Avoiding overdistention of the bladder
- Anesthetic paralysis during the resection of significant lateral wall lesions to lessen an obturator reflex response
- Large, bulky tumors and those that appear to be muscle invasive are often best resected in a staged manner
TURBT: Majority of perforations are ____, but ____ is possible when tumors are resected at the dome.
Majority = extraperitoneal Dome = intraperitoneal
- The risk of tumor seeding from perforation appears to be low
- ** Bladder perforation during TUR does appears to be associated with greater risk of recurrence and worse disease-free survival in a series published by Comploj et al. (2014)
TURBT: Extraperitoneal bladder perforation during TURBT can typically be managed ____. Intraperitoneal perforation is less likely to close spontaneously and usually requires ____.
Extraperitoneal = prolonged urethral catheter drainage.
Intraperitoneal = open or laparoscopic surgical repair.
In the setting of high-grade T1 tumors, ____ is recommended within ____ of initial TURBT based on the well- established risk of identifying worse prognostic findings or upstaging to muscle-invasive disease in up to ____% of repeat TURBT specimens.
Repeat TURBT
6 weeks
25-30% of repeat TURBT specimens
- This is especially important if no muscle is identified on initial pathology, where repeat resection of patients with T1 disease can identify upstaging to muscle-invasive disease in up to 49% of cases
The efficacy of BCG in preventing recurrence and progression appears to be higher in patients with high-grade papillary tumors and CIS if ____.
a restaging TURBT was performed before instillation of BCG.
If residual stage T1 is noted on repeat TURBT, risk of progression has been demonstrated to be as high as ___, thereby suggesting potential benefit of ____ in these patients.
80%
Early cystectomy
AUA guidelines recommend ____, within ____ of the initial TURBT in patients with incomplete initial resection, and patients with stage T1 disease. These guidelines also recommend consideration of repeat TURBT in patients with high-risk, high- grade Ta tumors
repeat TURBT of primary tumor site, to include muscularis propria
6 weeks
The current consensus is that random biopsies are not indicated in _____, but there remains no consensus with regard to patients with high-grade disease, and many urologists perform random biopsies in this setting particularly if urine cytology is positive.
in low-risk patients (i.e., those with low-grade papillary tumors and negative cytology)
Can you perform TURP and TURBT at the same setting?
YES, if bladder tumor is low-grade. Traditional teaching is that TURP and TURBT of a low-grade bladder tumor may be performed at the same setting but that resection of a high-grade bladder tumor should not be performed coincident to TURP to avoid tumor seeding and possible intravasation of tumor cells likely to metastasize.
*Despite anecdotal reports of low- grade tumors implanting in the prostatic urethra after simultaneous resection, this risk appears to be small
Laser Resection
The most significant complication of laser therapy is ____.
Forward scatter of laser energy to adjacent structures, resulting in perforation of a hollow, viscous organ such as overlying bowel.
**Limiting energy to 35 W precludes exceeding 60°C on the outer bladder wall, minimizing the risk of perforation
Many patients with ____ can be managed safely in the office setting with use of diathermy or laser ablation.
Small (typically <0.5–1 cm), low-grade recurrences
** Instillation of viscous or injectable 1% to 2% lidocaine mixed with bicarbonate through a catheter and a dwelling time of 15 to 30 minutes yields mucosal analgesia, although pain with fulguration of 1- to 5-mm tumors is often acceptable without analgesia.
*** many small, low-grade tumors can be safely observed until they exhibit significant growth because of the minimal risk of progression
BLC: _____ accumulate preferentially in neoplastic tissue. Under blue light they emit red fluorescence.
Dye: _____
Photoactive porphyrins
Hexaminolevulinic acid
***When blue light technology is used, small papillary tumors and almost one-third more cases of CIS overlooked on cystoscopy are identified
NBI: NBI light is composed of two specific wavelengths that are absorbed by hemoglobin; ____ penetrates only the superficial mucosal layers, whereas _____ penetrates more deeply.
Dye: _____
415-nm light = superficial mucosal layers
540-nm light = deeper layers
Dye: NONE
*** Narrow band imaging (NBI) is an optical image enhancement technology intended to improve the visibility of blood vessels inherent to neoplastic processes.
- Initial studies suggest that about 13% more tumors could be diagnosed by NBI
It is believed that _____ immediately after transurethral resection is responsible for many early recurrences.
Initial tumors are most commonly found on the ____ of the bladder, whereas recurrences are often located near ____ as a result of “flotation”.
Thus intravesical chemo- therapy to kill such cells before implantation has been used for decades.
Tumor cell implantation
Initial tumors: floor and lower sidewalls
Recurrences: near the dome, due to “flotation”
____ appears to be the most effective adjuvant intravesical chemotherapeutic agent perioperatively.
A single dose administered within ____ lessens recurrence rates, whereas a dose ____ does not
Mitomycin C (MMC) Within 6 hours lessens recurrences 24 hours later does NOT
** MMC maintenance therapy does NOT reduce the risk further (therefore, walang MMC maintenance)
Phase III RCT by SWOG: Gemcitabine demonstrated a _____% reduction in the likelihood of tumor recurrence with a very favorable side-effect profile. Hence gemcitabine remains an alternative option for perioperative intravesical chemotherapy.
34% reduction
Although _____ are the most common complications of postoperative instillation.
Chemotherapy should be withheld in patients with _____.
BCG can NEVER be safely administered immediately after TUR because the ____.
Local irritative symptoms
Extensive resection or when there is concern about perforation.
BCG immediately after TUR: Risk of bacterial sepsis and death is high.
Intravesical BCG: Treatments are typically started _____ after tumor resection, allowing time for re-epithelialization of the bladder after TURBT, thereby minimizing the potential for intravasation of live bacteria.
A ____ is usually performed immediately before instillation.
In the event of a _____, the treatment should be delayed for at least several days.
2 to 4 weeks
UA, to further confirm absence of infection or significant bleeding to decrease the likelihood of systemic uptake of BCG.
Traumatic catheterization
BCG: After instillation, the patient should retain the solution for at least _____.
Some clinicians have advocated that the patient turn from side to side to bathe the entire urothelium, but there is _____.
_____ before instillation limits dilution of the agent by urine and facilitates adequate retention of the agent for 2 hours
1 to 2 hours
NO scientific support for this practice
Fluid, diuretic, and caffeine restriction
BCG Mechanism of Action: _____
Initial step: _____
Intravesical immunotherapy results in a robust local immune response characterized by induced expression of cytokines in the urine and bladder wall and by an influx of granulocytes and mononuclear and dendritic cells.
Initial step: direct BINDING TO FIBRONECTIN within the bladder wall, subsequently leading to direct stimulation of cell-based immunologic response and an antiangiogenic state.
BCG MOA: The observed pattern of cytokine induction with preferential upregulation of _____ reflects induction of a ____.
IFN-γ, IL-2, and IL-12
T-helper type-1 (Th1) response
** This immunologic response activates cell-mediated cytotoxic mechanisms believed to underlie the efficacy of BCG and other agents in the prevention of recurrence and progression
BCG tumor free response rates:
Initial: ____%
4 year durable response: ____%
10 years: ____%
BCG tumor free response rates:
Initial: 84%
4 year durable response: 50%
10 years: 30% free of tumor progression or recurrence
The current AUA guidelines panel recommends BCG as the preferred initial treatment option for _____ and as a potential option either up front or preferably after intravesical chemotherapy for _____.
High-risk bladder tumors
intermediate-risk tumors
Intravesical BCG can effectively treat residual papillary lesions but _____.
… should not be used as a substitute for surgical resection.
Impact of BCG:
Meta-analyses have concluded that BCG reduces ____.
The risk of progression
***Superior results with BCG were concentrated in trials using BCG maintenance therapy. In contrast, no chemotherapy trials have achieved a significant reduction in progression
SWOG Regimen:
__________
Estimated median recurrence-free survival was _____ in the maintenance arm and ____ in the control arm.
6-week induction course followed by 3 weekly instillations at 3 and 6 months and every 6 months thereafter for 3 years.
- 8 months
vs. - 7 months
Short-term use of a _____ such as _____ for 24 to 48 hour post-BCG can reduce the cystitis-related side effects of BCG instillation in up to ____% of patients with the most significant reduction in side effects grade II or higher seen in patients after the fourth instillation.
Quinolone antibiotic, such as ofloxacin or prulifloxacin
20%
Post-instillation use of quinolones also reduced treatment delays and discontinuations while not affecting recurrence or progres- sion rates.
- Many urologists use this routinely as part of BCG instillation protocol
ABSOLUTE Contraindications to BCG Therapy (6)
ABSOLUTE Contraindications to BCG Therapy (6)
Immunosuppressed and immunocompromised patientsa Immediately after transurethral resection on the basis of the risk
of intravasation and septic death
Personal history of BCG sepsis
Gross hematuria (intravasation risk)
Traumatic catheterization (intravasation risk) Total incontinence (patient will not retain agent)
RELATIVE Contraindications to BCG Therapy (5)
RELATIVE Contraindications to BCG Therapy (5)
Urinary tract infection (intravasation risk)
Liver disease (precludes treatment with isoniazid if sepsis
occurs)
Personal history of tuberculosis (risk theorized but unknown) Poor overall performance status
Advanced age
Management of BCG Toxicity: GRADE 1
Mild or moderate irritative voiding symptoms, mild hematuria,
fever <38.5°C
Assessment
Possible urine culture to rule out bacterial urinary tract infection
Symptom Management
Anticholinergics, topical antispasmodics (phenazopyridine), analgesics, nonsteroidal anti-inflammatory drugs
(Asymptomatic prostatic granulomas that occur after
BCG therapy can occasionally mimic prostate
cancer clinically and/or radiographically. There is
no evidence to support treatment in this setting
Management of BCG Toxicity: GRADE 2
Severe irritative voiding symptoms, hematuria, or symptoms
lasting >48 h
All maneuvers for grade 1, plus the following:
Assessment
Urine culture, chest radiograph, liver function tests
Management
Consider dose reduction to one-half to one-third of dose when instillations resume.
Treat culture results as appropriate.
Can also consider pre-treating with a single dose of isoniazid
before each subsequent instillation
Antimicrobial Agents
Administer isoniazid and rifampin orally until symptom resolution.
Also use vitamin B6 or pyridoxine.
Do not use monotherapy.
Observe for rifampin drug-drug interactions (e.g., warfarin). Monitor liver function tests.
Management of BCG Toxicity: GRADE 3
Allergic Reactions (Joint Pain, Rash)
Perform all maneuvers described for grades 1 and 2, plus the
following:
Isoniazid and rifampin, depending on response. Also use vitamin B6 or pyridoxine.
Solid Organ Involvement (Liver, Lung, Kidney)
Stop BCG instillations. Initiate antimycobacterial therapy with isoniazid, rifampin. If symptoms persist, consult with Infectious Disease specialist with expertise in anti- tuberculous therapy. Can add ethambutol.
Cycloserine often causes severe psychiatric symptoms and is to be strongly discouraged.
BCG is almost uniformly resistant to pyrazinamide, so this drug has no role.
Consider prednisone when response is inadequate or for septic shock (never given without effective antibacterial therapy).
_____ is the only chemotherapeutic agent approved by the FDA specifically for the intravesical treatment of papillary bladder cancer.
Thiotepa (triethylenethiophosphoramide)
** In the NCCN Guidelines, it is NOT recommended (does not appear to be effective).
_____ is anthracycline antibiotic that acts by binding DNA base pairs, inhibiting topoisomerase II, and inhibiting protein synthesis.
Doxorubicin (Adriamycin)
** In a review, doxorubicin demonstrated a 13% to 17% improvement over TUR in preventing recurrence but no advantage in preventing tumor progression (15.2% vs. 12.6%)
____ is a semisynthetic analogue of doxorubicin that was approved by the FDA for treatment of BCG-refractory CIS in patients who cannot tolerate cystectomy;
Valrubicin
** In a cohort of 90 patients with BCG-refractory CIS, only 21% demonstrated a complete response.
Optimization of MMC delivery can result in halving of the recur- rence rate in some studies.
What are the ways to optimize MMC delivery?
Eliminating residual urine volume
Fasting overnight
Sodium bicarbonate to reduce drug degradation
Increasing concentration to 40 mg in 20 mL
Electromotive intravesical MMC (4-7 fold improvement in delivery)
Synergo-RITE (intravesical heating/chemohyperthermia)
Hyperthermic intravesical chemotherapy (HIVEC)
Electromotive intravesical MMC
The electromotive current is usually delivered as a pulsed current of 40 to 60 mA/sec to a maximum of 20 mA over 30 minutes through two cathode electrodes placed over the gel-smeared skin of the lower abdominal wall.
Synergo-RITE
Heating the bladder along with mitomycin instillation to incite a mild inflam- mation of the bladder wall, which potentiates the action of mitomycin but can also improve the effectiveness of BCG.
The interior of the bladder can be heated to a temperature of about 42°C using radiofrequency needles emerging from the tip of a urethral catheter.
Intravesical heating enhances the absorption and activity of mitomycin C similar to when the electric current is delivered transabdominally.
