follows:

a.established predictive factor for response to BCG therapy.

b.independent predictor of tumor progression for patients with pT1G3 disease.

c.stronger predictive value than grade for pTa tumors.

d.of no clinical value at present.

e.prospective validation required.

.Which of the following disease entities is least common?

a.pTa low grade

b.pTa high grade

c.pT1 high grade

d.CIS of any form

e.pT2-3

.The most important factor determining the long-term impact of BCG on progression is:

a.using a full dose with each instillation.

b.adding interferon.

c.maintenance therapy.

d.rolling side to side to ensure that BCG covers the entire urothelium.

e.washing the toilet with bleach after voiding each dose.

Answers

1.a. Initial presentation of a solitary 3.0 cm, low-grade–appearing tumor on the posterior bladder wall. Postoperative intravesical chemotherapy should be considered for most cases of new, apparently low-grade non– muscle-invasive bladder cancer because it has been shown to reduce recurrence rates and improve outcomes for this disease. One major exception is the patient in whom an extensive resection has been performed or whenever there is a possible perforation. In these patients intravesical chemotherapy should be withheld due to concern about local extravasation and absorption. The benefit of postoperative intravesical chemotherapy is reduced in patients with recurrent or multiple tumors, and there is no clear benefit in patients with high-grade disease.

2.b. Bacille Calmette-Guérin (BCG). BCG should never be given in association with known trauma to the urinary tract, such as after transurethral resection of a bladder tumor (TURBT), due to concern

over systemic absorption and sepsis. All of the other agents have shown efficacy in this setting with a favorable morbidity profile.

3.a. Sensitivity. Tumor markers such as BTA stat, NMP-22, and UroVysion (FISH) provide increased sensitivity, particularly for low-grade tumors. High specificity is the strength of urinary cytology. This approaches 90% to 100% in many series and has not been improved on with these other markers. Positive predictive value is highest for urinary cytology because the number of false positives is low. Put another way, if the cytology is positive, the patient usually has active disease.

4.b. 3% to 10%. Recurrence is common (50% to 70%) for patients with low-grade, pTa tumors, but progression to higher tumor stage is uncommon, occurring in about 5% to 10% of patients.

5.c. Lateral location, at approximately 4 o'clock or 8 o'clock. Resection along the lateral bladder wall posterolaterally places one in proximity to the obturator nerve, and this can lead to an obturator reflex. This can predispose to bladder wall perforation. In this situation, general anesthesia with complete paralysis is sometimes beneficial to allow the procedure to be performed in a safe and facile manner.

6.d. Radical cystectomy and neobladder urinary diversion. This patient should be strongly considered for radical cystectomy. Partial cystectomy is not a good option because of the presence of CIS, which indicates a high risk of field effect disease and subsequent recurrence. Deeper biopsies will risk perforation and would be unlikely to influence management. Understaging is common with tumors in diverticuli, and high-grade invasive tumors like this are best managed with radical cystectomy to ensure local disease control and optimize outcomes on a long-term basis.

7.c. Avoid cautery in this area. A stent should be avoided if possible to prevent theoretical risk of reflux of tumor cells into the upper tracts. In most cases this area can be resected, and most ureters will remain unobstructed as long as the orifice is identified and cautery is not used in this area. Preoperative placement of a nephrostomy tube is often unnecessary as long as renal function is stable. Many patients with hydronephrosis will have invasive disease and will be undergoing urinary diversion in the near future, and this will relieve the obstruction. Hence, temporary nephrostomy tube placement is usually not required.

8.d. a and c. Patients with pT1 tumor for whom the muscularis propria was not identified are understaged about 50% of the time and a repeat resection is

risk superficial bladder cancer treated with intravesical BCG therapy is derived primarily for the experience of Memorial Sloan Kettering (Cookson et al, 1997).* In this series, 50% of patient progressed, and one third died of cancer progression. Approximately one third developed disease in the prostatic fossa or upper tracts, and only 27% survived with an intact bladder. Such data should be considered when counseling patients about treatment options for high-risk disease.

.d. 30% to 50%. The risk of understaging of a pT1 high-grade bladder tumor is approximately 30%, but it is even higher if there is no muscularis propria in the specimen. Altogether, the risk is about 30% to 50% in this high-risk

patient population.

.a. Not indicated. The incidence of upper tract tumor associated with pTaG1 bladder cancer is extremely low (0.3% to 2.3%), and current consensus is that upper-tract imaging is not indicated in this patient population (Oosterlinck et al, 2005). If hematuria is present, however, upper-tract imaging is indicated for its evaluation regardless of the finding of bladder tumor.

.e. Are not indicated in most cases. The yield of random bladder biopsy in patients with low-grade, low-stage bladder tumors and a negative cytology is very low and is not indicated unless high-risk features are present.

.e. Higher than 45%. Untreated CIS is very high risk (> 50%) for progressing to muscle-invasive disease. Even patients with a complete response to intravesical BCG will experience progression in 30% to 40% of cases on longitudinal follow-up (Sylvester et al, 2005).

.e. Prospective validation required. Almost all studies of p53 as a prognostic marker have been retrospective to date. Although promising, this marker will require prospective validation before it can be generally used for clinical decision making. However, the balance of available data has been promising,

and the use of this marker for decision making in very challenging cases has been advocated by many in this field. Most studies suggest that p53 is not a good predictor of response to BCG therapy, and it is clearly not better than grade for predicting outcomes for pTa disease. Its ultimate role for predicting progression for pT1 high-grade tumors is not well defined at present.

.b. pTa high grade. pTa low grade represents 50% to 70% of all non– muscle-invasive bladder tumors and is the most common of these entities. CIS is commonly associated with high-grade tumors and, overall, is found in approximately 10% to 20% of non-muscle-invasive bladder tumors. pT1 high grade is found in approximately 20% of patients with non–

muscle-invasive bladder tumors. pT2-3 represents approximately 20% of all bladder cancer patients. pTa high grade is often misclassified, and in reality only represents approximately 5% to 10% of all non–muscle invasive tumors (Sylvester et al, 2005).

.c. Maintenance therapy. Maintenance therapy is the only proven scenario demonstrating reduction of tumor progression. Dose reduction studies appear to support similar benefit for lower doses, which are usually better tolerated if side effects are identified with full dosing. Interferon is incrementally beneficial in certain circumstances. Options d and e are both without scientific basis, but are commonly recommended.

Chapter review

1.Low-grade Ta bladder cancer recurs at a rate of 50% to 70% and progresses in approximately 5%.

2.High-grade T1 lesions recur in more than 80% of cases and progress in 30% to 50%.

3.The most important risk factor for progression is grade.

4.A nodular or sessile appearance suggests deeper invasion.

5.Lymphovascular invasion increases the risk of muscularis propria invasion.

6.Hydronephrosis is often but not always associated with muscularis propria invasion.

7.Papillary low-grade tumors can often be removed with the resectoscope loop without the use of electrocautery.

8.A separate biopsy of the base of the tumor should be obtained after initial resection.

9.Tumors about the ureteral orifice should be resected with pure cutting current.

10.Mitomycin C is the most effective adjuvant intravesical therapy and, when used, should be administered within 6 hours of tumor resection. Postoperative intravesical chemotherapy should be considered for most cases of new, apparently low grade non–muscle-invasive bladder cancer because it has been shown to reduce recurrence rates and improve outcomes for this disease. It does not have a benefit in high-grade disease.

11.All chemotherapy should be withheld when there is an extensive resection or when there is a concern that a perforation may have

occurred.

12.BCG should never be administered immediately following a tumor resection.

13.The mechanism of action of BCG is by initially binding to fibronectin and then the production of multiple cytokines.

14.After induction therapy, patients receiving maintenance BCG have a statistically significant decrease in recurrence rate compared with those receiving induction therapy alone.

15.BCG may delay the progression of high-risk bladder cancer; however, ultimately there may be no difference in long-term survival.

16.Quinolones should not be administered with BCG.

17.BCG plus interferon-α has a potential role regardless of prior BCG experience.

18.Risk factors for progression in patients with non–muscularis propriainvasive bladder cancer include high-grade tumors invading deeply into the lamina propria, lymphovascular invasion, associated diffuse CIS, bladder neck invasion, and disease that is refractory to initial therapy.

19.Although upper tract disease occurs in 0.8% to 4% of patients, when it does occur, the mortality rate is 40% to 70%.

20.Urothelial cancers are subdivided into papillary urothelial neoplasia of low malignant potential (old grade 1), low grade (old grade 2), and high grade (old grade 3).

21.Random biopsies in patients with normal-appearing urothelium is controversial; however, most agree that such biopsies are not indicated in those with low-risk disease.

22.BCG-refractory patients are at high risk for progression and should be considered for cystectomy.

23.For patients who have failed BCG, a second course results in 30% to 50% response rate.

24.Tumor recurrence on the initial 3-month surveillance cystoscopy and number of tumors on initial cystoscopy are strong predictors of recurrent disease.

25.Cytology is positive in one third of patients with low-grade disease and two thirds of patients with high-grade disease.

26.Megadose vitamins have shown promise in reducing recurrences of urothelial tumors.

27.BTA stat, NMP-22, and UroVysion (FISH) provide increased sensitivity,

particularly for low-grade tumors. High specificity is the strength of urinary cytology. If the cytology is positive, the patient usually has disease.

28.BGC is contraindicated in patients with liver disease (isoniazid cannot be given if they develop BCG sepsis), a personal history of TB, total incontinence (they cannot retain the BCG, so efficacy would be poor), and immunosuppression (BCG's mechanism of action is to stimulate an immune response). Other contraindications include disrupted urothelium, gross hematuria, or active or persistent symptomatic UTI.

29.Long-term outcomes for a patients with high-risk superficial bladder cancer treated with intravesical BCG therapy is derived primarily from the experience of patients at Memorial Sloan Kettering. In their series 50% of patients progressed, and one third died of cancer progression. Approximately one third developed disease in the prostatic fossa or upper tracts, and 27% survived with an intact bladder.

30.Untreated diffuse CIS is very high risk for progressing to muscle invasive disease. Even patients with a complete response to intravesical BCG will experience progression in 30% to 40% of cases on longitudinal follow-up.

* Sources referenced can be found in Campbell-Walsh Urology, 11th Edition, on the Expert Consult website.