In 1999, bladder cancer was newly diagnosed in

REVIEW INTRAVESICAL THERAPY FOR BLADDER CANCER ASHISH M. KAMAT AND DONALD L. LAMM In 1999, bladder cancer was newly diagnosed in about 54,200 patients, and 12,100 patients died of this disease in the United States. Despite an increase in the incidence of bladder cancer, mortality rates have declined by 8% between 1980 and 1995. 1 The 5-year relative survival rate for patients with superficial bladder cancer is now about 95% largely because of improvements in intravesical therapy. Bacille Calmette-Guérin (BCG) immunotherapy, the most effective treatment and prophylaxis for superficial transitional cell carcinoma (TCC), decreases tumor recurrences, disease progression, and bladder cancer-specific mortality. Intravesical chemotherapy reduces short-term tumor recurrence rates but has failed to impact disease progression or survival. Newer immunologic and chemotherapeutic agents, advances in photodynamic therapy (PDT), and other measures to boost the efficacy of intravesical therapy for bladder cancer are promising. In this review, we highlight the advances in intravesical therapy in the management of TCC of the bladder. INTRAVESICAL IMMUNOTHERAPY From the Department of Urology, West Virginia University School of Medicine, Morgantown, West Virginia Reprint requests: Ashish M. Kamat, M.D., Department of Urology, Robert C. Byrd Health Sciences Center, West Virginia University, P.O. Box 9251, Medical Center Drive, Morgantown, WV 26506-9251 Submitted: July 28, 1999, accepted (with revisions): September 23, 1999 BCG IMMUNOTHERAPY BCG is a live, attenuated vaccine that has emerged as the most effective agent for the treatment of superficial bladder cancer and was approved by the U.S. Food and Drug Administration (FDA) in 1990 for carcinoma in situ (CIS). BCG is a nonspecific immune system stimulant and requires an immunocompetent host to elicit its effects. 2 Of primary importance is the strong TH1 cellular immune response elicited by BCG. It activates macrophages, T lymphocytes, B lymphocytes, and BCG-activated killer cells. It stimulates lymphokine and interferon production and enhances natural killer cell activity. Recent data suggest that BCG might also exert its effect through the nitric oxide pathway. 3 Table I summarizes six studies showing a reduction of tumor recurrence from an average of 67% in controls to 29% with BCG. 4 9 In Lamm s study, 4 the mean time to recurrence increased from 24 to 48 months (P 0.01). Herr et al. 5 found a prolongation in the time to muscle invasion or metastasis with a reduction in mortality from 32% to 14% with BCG. Cystectomy was required in 42% of controls compared with 26% with BCG treatment, and the median time to cystectomy increased from 8 months (control) to 24 months (BCG). 10 In a subsequent report with 3 years additional follow-up, cancer deaths were reduced from 37% to 12% (P 0.01). 6 Pagano et al. 7 studied 133 randomized patients, and stage progression to T2 or higher occurred in 17% of controls versus 4% of those treated with BCG (P 0.001). Long-term follow-up studies have frequently demonstrated prolonged protection from tumor recurrence and reduction in tumor progression and mortality. The observed reduction in tumor recurrence ranges from 20% to 65%, with an average benefit of 40%, and the mean rate of progression is reduced from 28% in controls to 14% in those receiving BCG. 11 The superiority of BCG is most evident in the treatment of patients with CIS. An analysis of data from six prospective Phase II trials found a complete remission in 76% of BCG-treated patients. Importantly, the cystectomy rate was only 11% in responders versus 55% in the nonresponders (P 0.0001), and the time to cystectomy was increased from 31 to 74 months. 12 With optimal BCG immunotherapy, the complete response (CR) rate can be increased to 87%. 13 Residual CIS at the 3-month evaluation is not necessarily an indication for cystectomy or change in treatment. In the SouthWest Oncology Group study, the CR rate increased from 58% to 69% between 3 and 6 months without additional BCG. With three additional weekly BCG instillations, the CR rate increased from 55% to 84% at 6 months (P 0.01). 14 Herr et al. 10 reported that 32% of patients showing the presence of disease at 3 months after a 6-week course of BCG proceeded to a disease-free state by 2000, ELSEVIER SCIENCE INC. UROLOGY 55: 161 168, 2000 0090-4295/00/$20.00 ALL RIGHTS RESERVED PII S0090-4295(99)00463-X 161

Investigators TABLE I. Comparison of recurrence after TURBT alone vs. after BCG therapy Total Control TURBT Alone Recurrence Treatment BCG Therapy Recurrence P Value Lamm, 4 1985 57 27 14 (52) 30 6 (20) 0.001 Herr et al., 5 1985 86 43 41 (95) 43 18 (42) 0.001 Herr et al., 6 1991 49 26 26 (100) 23 8 (35) 0.001 Pagano et al., 7 1991 133 63 52 (83) 70 18 (26) 0.001 Melekos et al., 8 1993 94 32 19 (59) 62 20 (32) 0.02 Krege et al., 9 1996 224 122 56 (46) 102 26 (26) 0.01 Total 643 313 208 (67) 330 96 (29) KEY: TURBT transurethral resection of bladder tumor; BCG bacille Calmette-Guérin. Numbers in parentheses are percentages. 6 months. The response to BCG at 6 months can be used as a predictor of prognosis, with the number of patients developing progressive disease being significantly higher among the nonresponders. 15 Intravesical BCG can be used to treat CIS involving the prostatic urethral mucosa or prostatic ducts in the absence of stromal invasion. Intravesical BCG is not recommended for the treatment of muscle invasive disease. In a report of 13 patients with Stage T2 or higher bladder cancer treated with BCG, only 1 of 13 was disease free; 10 of 13 patients developed systemic disease and 7 patients died of metastases. 16 Although most accept that a single 6-week course of BCG is suboptimal, maintenance therapy has been controversial. Single monthly or quarterly BCG instillations are not superior to standard induction. 17 Kavoussi et al. 18 demonstrated that a second 6-week course of BCG could increase the efficacy from 36% to 65% in those treated prophylactically and from 37% to 71% for those treated for CIS (overall increase in response from 37.5% to 59.6%). Lamm et al. 19 have proposed an alternative 6 3 regimen that is superior to the 6 6 regimen. Patients receive a 6-week induction course of BCG and then three weekly instillations at 3 and 6 months and every 6 months thereafter for 3 years. With administration of three weekly BCG treatments 6 weeks after induction, 87% of patients with CIS had a CR and 83% of patients with CIS or rapidly recurring Ta or T1 TCC remained tumor free. Urinary cytokines peak in most patients after the initial sixth BCG installation, but patients previously exposed to BCG induction have optimal stimulation at 3 weeks, and continued BCG administration suppresses immune response and increases toxicity. Many patients in whom the 6 6 regimen failed may have received too much rather than too little BCG. To further reduce tumor recurrence, high doses of vitamins A, B 6, C, and E versus recommended daily allowances were studied. High-dose vitamins significantly reduced tumor recurrence, with 5-year estimates of tumor recurrence of 91% in the recommended daily allowance arm and 41% in the megadose arm. 20 BCG is generally well tolerated, although symptoms of cystitis do occur in up to 90% of patients. 21 The BCG dose can be reduced to one third, one tenth, one thirtieth, or even one one-hundredth as needed to prevent side effects. Isoniazid 300 mg daily relieves symptoms but prophylactic isoniazid is not advisable, since it can decrease the immune response to BCG in animal models. 22 BCG sepsis has been observed in approximately 0.4% of patients. The addition of prednisolone reproducibly improves survival in the animal model of BCG sepsis. 23 There is no evidence that BCG therapy is contraindicated in patients with vesicoureteral reflux. 24 BCG should not be given to immunocompromised patients or after a traumatic catheterization. OTHER IMMUNOTHERAPEUTIC AGENTS Interferons. Interferons are host-produced glycoproteins that mediate host immune responses in a dose-dependent fashion. 25 Torti et al. 26 reported a 25% CR in 16 patients with recurrent papillary TCC and a 32% CR and 26% partial response (persistent positive cytologic findings) in 19 patients with refractory CIS. Adverse reactions after intravesical interferon-alpha therapy are mild and include flu-like symptoms. In a recent review, Belldegrun et al. 27 concluded that recombinant interferon-alpha has an important role in the treatment of superficial TCC, particularly as secondline therapy after failure of BCG or chemotherapy and that it may have synergistic effects when combined with chemotherapy or BCG. Keyhole Limpet Hemocyanin. Keyhole limpet hemocyanin (KLH), a highly antigenic respiratory pigment of the mollusc Megathuria crenulata, is a nonspecific immune stimulator. Lamm et al. 28 reported a CR in 45% of patients and a partial response in 21% of patients with KLH for 6 weeks. The best responders were patients with CIS: 58% had a CR. Jurincic et al. 29 reported that KLH (14% 162 UROLOGY 55 (2), 2000

recurrence) was better than mitomycin (39.1% recurrence) in the prevention of recurrent superficial TCC (P 0.05). Flamm et al. 30 reported no difference in efficacy between KLH and ethoglucid. The advantage of KLH is its apparent lack of toxicity. Bropirimine. Bropirimine is a low-molecularweight immunomodulator with a wide spectrum of immune stimulating activity. Sarosdy et al. 31 reported a 52% CR in patients treated for residual disease. The best responders were those without prior intravesical therapy; of these, 70% had a CR. Despite demonstrated antitumor activity and the advantage of oral administration, bropirimine is no longer available in the United States. INTRAVESICAL CHEMOTHERAPY Intravesical chemotherapy became popular in the 1960s when thiotepa was shown to reduce tumor recurrence and eliminate one third of papillary tumors. 32 Unlike systemic chemotherapy, responses to topical chemotherapy are proportional to the drug concentration rather than the drug dose. 33 Responses are also dependent on the duration of exposure, which is short and limited by bladder capacity. Cytotoxic drugs are active against DNA in rapidly dividing cells. The drug is administered by way of a urethral catheter and left in the bladder for varying amounts of time. Although some urologists have the patient lie prone for 15 minutes to ensure contact of the drug with the urothelium at the dome, animal studies have suggested that this may not be necessary. 34 Table II summarizes several controlled studies that show the effect of intravesical chemotherapy on recurrence in patients undergoing transurethral resection of bladder tumor. MITOMYCIN C Mitomycin C is an antibiotic chemotherapeutic agent that causes cross-linking of DNA and inhibition of DNA synthesis. In treatment of Stage Ta and T1 disease, the CR averages 36% and the decrease in recurrence ranges from 19% to 42%. A single, immediate instillation of mitomycin C significantly decreases early tumor recurrence, but this benefit decreases with long-term follow-up, suggesting that mitomycin C does not impact the biology of low-risk bladder cancer. 35 Most mitomycin C instillation protocols have used 20 to 60 mg weekly for 6 to 8 weeks. Maintenance therapy has been unsuccessful, and evidence suggests that prolonged courses are not superior to short courses. 36 Mitomycin C is very expensive, and controlled trials have failed to show improved efficacy when compared with other intravesical chemotherapies. 37 Because of its high molecular weight, the incidence of systemic side effects is low. The major adverse effect of intravesical mitomycin C is chemical cystitis, which occurs in up to 41% of patients. In one series, decreased bladder capacity was observed to be as high as 22%, with 2 of 76 patients requiring cystectomy for severe bladder contracture. 38 Facial and palmar skin rash, palmar desquamation, and eosinophilic cystitis are also seen. Patients should be advised to avoid contact with their urine after instillation. THIOTEPA Thiotepa, an aziridine with alkylating activity, is the only intravesical chemotherapy specifically approved by the FDA for the treatment of papillary TCC. Thiotepa is effective in the treatment of residual tumor or CIS, resulting in a CR in one third of the patients. As a prophylactic agent, 6 of 11 randomized controlled studies demonstrated a statistically significant reduction in tumor recurrence. 11 The decrease in the percentage of recurrence averages 16%, with a range of 12% to 41%. If we eliminate the large Medical Research Council (MRC) study that used a dilute concentration (30 mg/60 ml) from Table II, the advantage of thiotepa is as high as those of newer, more expensive, chemotherapeutic agents. As with other chemotherapeutic agents, protocols using early administration have shown better results, and multiple treatments have no added benefit. Thiotepa is generally well tolerated. The major adverse effect of thiotepa is myelosuppression due to systemic absorption. The incidence of leukopenia ranges from 8% to 54% and that of thrombocytopenia from 3% to 31%. 39 Recent tumor resection, extensive tumor, or concurrent cystitis can markedly increase absorption. DOXORUBICIN Doxorubicin disrupts the cell by several mechanisms, including inactivation of DNA topoisomerase II and production of activated oxygen radicals. As seen in Table II, doxorubicin reduces tumor recurrence compared with surgery alone by an average of 16%. Again, the maximal benefit in reported controlled prophylaxis studies occurred with a single, early postoperative instillation, 40 and maintenance therapy did not provide any added benefit. Evidence from work in our laboratory suggests that the efficacy of doxorubicin may be enhanced by simultaneous administration of oral quinolone antibiotics. 41 The primary side effect seen with doxorubicin is chemical cystitis, causing symptoms of dysuria, frequency, and urgency in up to 50% of patients. EPIRUBICIN Epirubcin (4 -epidoxorubicin) is an epimer of doxorubicin. A recent trial demonstrated that a single dose of epirubicin given intravesically im- UROLOGY 55 (2), 2000 163

TABLE II. Investigators Effect of intravesical chemotherapy on recurrence in controlled studies of patients undergoing transurethral resection of bladder tumor Total Control (TURBT) Control Recurrence Chemotherapy Treatment Recurrence Difference % Recurred P Value* Thiotepa Burnand et al., 1976 51 32 31 (97) 19 11 (58) 39 0.001 Byar and Blackar, 1977 86 48 29 (60) 38 18 (47) 13 0.016 Nocks et al., 1979 42 22 14 (64) 20 13 (65) 1 NS Asahi et al., 1980 134 56 23 (41) 78 31 (40) 1 NS Schulman et al., 1982 209 104 72 (69) 105 62 (59) 10 NS Koontz et al., 1981 93 47 31 (66) 46 18 (39) 27 0.02 Zincke et al., 1983 58 28 20 (71) 30 9 (30) 41 0.002 Prout et al., 1985 90 45 43 (76) 45 29 (64) 12 0.05 MRCI, 1985 367 123 46 (37) 244 97 (40) 3 NS Netto et al., 1983 34 20 16 (80) 14 6 (43) 37 NS Hirao et al., 1992 93 48 22 (46) 45 7 (15) 31 0.0015 Total 1257 573 347 (61) 684 301 (44) 17 Doxorubicin Niijima et al., 1983 436 139 86 (62) 297 135 (45) 17 0.05 Zincke et al., 1983 59 28 20 (71) 31 10 (32) 39 0.01 Kurth et al., 1985 217 70 41 (59) 147 52 (35) 24 0.006 Rubben et al., 1988 220 82 50 (61) 138 77 (56) 5 NS Akaza et al., 1987 457 148 49 (33) 309 77 (25) 8 NS Abrams et al., 1981 57 28 25 (89) 29 23 (79) 10 NS Total 1446 495 271 (55) 951 374 (39) 16 Mitomycin C Huland and Otto, 1984 79 31 16 (52) 48 5 (10) 42 0.01 Niijima et al., 1983 278 139 86 (62) 139 79 (57) 5 NS Kim and Lee, 1988 43 22 18 (82) 21 17 (81) 1 NS Tolley et al., 1988 452 157 94 (60) 295 121 (41) 18.9 0.001 Krege et al., 1996 234 122 56 (46) 112 30 (27) 19 0.004 Solsona et al., 1999 121 64 8 (12) 57 6 (10) 2 NS Akaza et al., 1987 298 148 49 (33) 150 36 (24) 9 NS Total 1505 683 327 (48) 822 294 (36) 12 Epirubicin Oosterlinck et al., 1983 399 205 84 (41) 194 56 (29) 12 0.0152 Melekos et al., 1993 99 32 19 (59) 67 27 (40) 19 NS Igawa et al., 1996 75 32 22 (69) 43 26 (60) 9 NS Raitanen et al., 1995 51 19 17 (90) 32 24 (75) 15 NS Rajala et al., 1999 134 66 40 (60) 68 23 (35) 15 0.001 Total 758 354 182 (51) 404 156 (39) 12 KEY: TURBT transurethral resection of bladder tumor; NS not significant. Numbers in parentheses are percentages. *Pvalue as reported by the original investigators. Length of follow-up and risk factors vary from study to study; therefore, statistical comparisons, other than those reported by the original investigators, were not appropriate and thus are not reported. Averages are presented for interest only. mediately after tumor resection was safe and significantly decreased tumor recurrence from 60% in those with resection alone to 34% in those treated with epirubicin. 42 The average benefit over transurethral resection of bladder tumor is 12% (Table II). As with other chemotherapeutic agents, recent studies have shown that maintenance instillation of epirubicin does not have any added benefit. 43 Epirubicin is not, at the time of writing, available in the United States, but approval for lung cancer has been sought. VALRUBICIN The FDA recently approved valrubicin for the treatment of BCG refractory CIS. Although valrubicin does not bind strongly to DNA, a principal mechanism of its action mediated by valrubicin metabolites is interference with the normal DNA 164 UROLOGY 55 (2), 2000

breaking-resealing action of DNA topoisomerase II. Greenberg et al. 44 demonstrated that six weekly intravesical doses of valrubicin resulted in a CR in 13 patients with superficial TCC. In a study of 87 patients with BCG refractory CIS who received six weekly instillations of 800 mg of valrubicin, a CR, as documented by bladder biopsies and cytologic examination, was seen in 21% of patients at a median follow-up of 18 months. 45 Patients should be informed that valrubicin has been shown to induce CRs in only about 1 in 5 patients and that delaying cystectomy could lead to the development of metastatic bladder cancer. It must be remembered that BCG refractory CIS is a dangerous disease, and cystectomy is generally curative. However, valrubicin is appropriate when other comorbid factors make the patient a poor risk for radical cystectomy. PHOTODYNAMIC THERAPY PDT involves intravenous administration of a photosensitizer such as Photofrin (sodium porfimer), which is a mixture of hematoporphyrinderived oligomers. When the photosensitizer is activated by laser light, selective tumor kill occurs by way of direct superoxide radical-mediated cytotoxicity, vascular endothelial damage, and a local inflammatory response. Several investigators have reported the effectiveness of PDT in the treatment of patients with recurrent superficial bladder cancer, with complete and partial response rates of 41% and 39%, respectively. 46 In 58 patients with resistant TCC, including Ta, T1, and refractory CIS of the urinary bladder reported by Nseyo et al., 47 the CR rate was 84% and 75% for residual resistant papillary TCC and refractory CIS, respectively; and 90% of patients treated prophylactically were without recurrence at 3 months. PDT treatment induces dose-related symptoms of cystitis. The most severe adverse reaction is permanent bladder contracture, which has been reported in 10% of patients. To avoid skin photosensitivity reactions, solar isolation is required for up to 6 weeks after Photofrin injection. Introduction of new photosensitizers and modifications of laser delivery techniques could lead to increased application of PDT in the near future. RECOMMENDATIONS INDICATIONS FOR INTRAVESICAL THERAPY At the time of presentation, most bladder tumors are superficial. The initial treatment is complete transurethral resection of the tumor. Intravesical therapy is not required in every patient. Low-grade Ta lesions have a low progression rate of 7% at 7 years and, in the absence of other risk factors, can be treated by resection alone. Even so, the European Organisation for Research and Treatment of Cancer (EORTC) reported a 12% reduction in tumor recurrence in such patients when treated with a single, early postoperative instillation of epirubicin. 48 Multifocal Ta disease is a relative indication for intravesical therapy. 49 Infrequent recurrences of low-grade Stage Ta disease can be treated with repeated resections; however, when recurrence is noted within 2 years, intravesical therapy should be considered. The conclusion that low-grade tumors are not a threat is erroneous; of all patients progressing to muscle invasive disease, 25% initially had grade 1, Stage Ta or T1 disease. 50 About 45% of newly diagnosed cancers are high-grade lesions and have a higher likelihood of recurrence and muscle invasion than similarly staged lowgrade lesions. 51 Long-term follow-up of patients with Stage T1, grade 3 TCC of the bladder treated locally is associated with a 52% progression rate and a median progression-free survival of 12.7 years. Up to 25% of patients will die of the cancer in the first 5 years and 10% of patients after 5 to 15 years. 52 Regardless of stage, grade 3 tumors recur in 70% of patients and have a 45% risk of progression at 3 years. Therefore, patients with grade 3 disease, regardless of tumor stage, should be offered intravesical therapy. Although grade is an important cofactor when considering the progression of T1 lesions, T1 tumors have an overall progression rate of 29% and warrant intravesical therapy. Other indications for adjuvant intravesical therapy include positive cytologic findings after transurethral resection of bladder tumor, recurrent tumors, extravesical urothelial tumors, and the presence of urothelial dysplasia. CIS should be considered a highly aggressive malignancy with a tendency to invade and metastasize. CIS has a high risk of disease progression and increases the risk of disease progression significantly to 65% at 5 years. 53 Hence, even a small focus of CIS is a definite indication for intravesical therapy. Intravesical immunotherapy has replaced cystectomy as the primary treatment for diffuse CIS, with CR rates reaching 84%. Prostatic urethral involvement with CIS carries a high risk of progression and must be treated aggressively. Transurethral resection is needed to carefully stage the disease and open the bladder neck so that BCG may bathe the prostatic urethra after intravesical instillation. Intravesical BCG immunotherapy has effectively eliminated the need for cystectomy in many of these patients. 13 The lower ureter and prostatic urethra remain relatively protected from the action of intravesical therapy, and continued surveillance in patients with high-grade TCC must include upper tract imaging and prostatic urethral biopsies at regular intervals. UROLOGY 55 (2), 2000 165

CHOICE OF AGENT An analysis of practice patterns revealed that most community urologists (in Miami) used BCG to treat superficial TCC. 54 This is not true in Europe, where BCG is usually reserved for high-risk patients, with intravesical chemotherapy being the first choice of most urologists. We believe that intravesical BCG is the most effective treatment for superficial bladder cancer, especially CIS. Controlled comparative studies have shown that BCG is superior to thiotepa, doxorubicin, or mitomycin C. 55 As seen from Table II, thiotepa, doxorubicin, mitomycin C, epirubicin, and ethoglucid reduce the short-term recurrence rate by an average of 17%, 16%, 12%, 13%, and 31%, respectively. However, no consistent long-term reduction has been found in recurrence or reduction in disease progression or mortality. Prout et al. 56 demonstrated equal 5-year recurrence rates in patients treated with thiotepa versus surgery alone. Akaza et al. 57 reported a 6-year follow-up on a prospective randomized study and found no difference between chemotherapy and control with respect to the recurrence index or the mean time between recurrences. Controlled comparisons have also failed to demonstrate any difference among individual agents, with the exception of ethoglucid and doxorubicin. 58 The inability of intravesical chemotherapy studies to demonstrate any long-term benefit was taken as a challenge by investigators in the EORTC and MRC studies. In a combined metaanalysis of 2535 patients with Stage Ta and T1 TCC enrolled in six Phase III randomized trials, a significant (P 0.01) reduction in recurrence was seen in 1629 patients treated with thiotepa, teniposide, doxorubicin, epirubicin, mitomycin C, or oral pyridoxine compared with 906 patients treated with transurethral resection alone. Patients were monitored for up to 18 years (median 7.7). Although the overall reduction in tumor recurrence was only 7%, additional improvement might have been observed had control patients not later received intravesical therapy. 59 Unfortunately, no clear advantage of adjuvant treatment was shown with respect to progression, time to appearance of distant metastases, or duration of survival. Other studies of intravesical chemotherapy have also failed to demonstrate any effect on disease progression. In an analysis of 3899 patients enrolled in 22 randomized prospective controlled studies, Lamm et al. 60 found that progression occurred in 7.5% of those receiving intravesical chemotherapy and 6.9% of those treated by surgery alone. Intravesical chemotherapy has some efficacy in the management of CIS, with reported overall CR rates of 34%. BCG immunotherapy, on the other hand, does reduce long-term tumor recurrence, tumor progression, and mortality from superficial TCC. BCG immunotherapy reduces tumor recurrence by an average of 40% compared with the 14% average reduction with chemotherapy. The effect of immunotherapy is long lasting and includes a reduction in disease progression. The SouthWest Oncology Group reported that for patients with superficial tumors without CIS, the estimated probability of being disease free at 5 years was 17% after doxorubicin compared with 37% after BCG (P 0.015). The median time to treatment failure was 10.4 and 22.5 months, respectively. For patients with CIS, the CR probability estimate was 34% for doxorubicin and 70% for BCG (P 0.001); the median time to treatment failure was 5.1 and 39 months, respectively. The probability of being disease free at 5 years among the patients with CIS was 18% after treatment with doxorubicin and 45% after BCG therapy. 13 Melekos et al. 61 showed that BCG had a clear advantage with regard to prophylaxis of Stage T1 and high-grade tumors at a median follow-up of 33 months. Cookson et al. 62 reported that 91% of patients with high-risk Stage T1 TCC who received intravesical BCG immunotherapy were disease free at a mean follow-up of 59 months. Maintenance BCG has further improved the long-term protection from tumor recurrence in patients with Stage Ta and T1 disease. Furthermore, not all tumors that recur after BCG immunotherapy proceed to muscle invasion or metastasis, and some patients may be treated safely with repeated endoscopic resection and intravesical therapy, with cystectomy delayed until objective progression is evident. Such an approach can yield survival equal to that in patients treated with early cystectomy and may result in longer intervals of bladder preservation in a select subset of patients in whom BCG fails locally. 63 Several theories have been put forward to explain why BCG immunotherapy has an advantage over chemotherapy with respect to long-term recurrence and disease progression. BCG produces a mucosal infection that can persist for many months. The continued replication of organisms provides a longer duration of action than chemotherapy, which decreases in concentration rapidly after instillation and is finally removed with voiding 2 hours after instillation. Since intravesical chemotherapeutic agents are active against rapidly dividing tumor cells, the concept of preventing tumor recurrence with chemotherapy is illogical unless one assumes the presence of occult malignancy. Immunotherapy also has the potential to induce specific immunity to bladder tumors and prevent de novo tumor recurrence. Finally, BCG is able to penetrate deep within the detrusor muscle and has even been observed in pelvic lymph nodes after instillation; chemotherapy is dependent on simple diffusion and penetrates to the depths of tumor extension poorly. However, there appears to be one situation in which intravesical chemotherapy holds a clear ad- 166 UROLOGY 55 (2), 2000

vantage over BCG. As previously mentioned, a single dose of intravesical chemotherapy immediately after tumor resection is safe and significantly decreases tumor recurrence. This is probably due to the action of the agent against residual tumor cells and prevention of reimplantation of exfoliated tumor cells. 64 It must be remembered, however, that not only does immediate intravesical immunotherapy have no added benefit over resection alone, it can lead to devastating consequences, such as BCG sepsis. CONCLUSIONS The management of superficial bladder cancer has evolved during the past 15 years, concurrent with improved understanding of the biology of superficial TCC. BCG immunotherapy not only reduces recurrences of superficial TCC but also decreases stage progression, cystectomy rates, and disease-specific mortality. Controlled comparative studies have shown that BCG is superior to intravesical chemotherapy, especially in CIS where a CR is seen in more than 70% of patients and the 5-year disease-free interval averages 40%. We believe that BCG is superior to chemotherapy even in the treatment of patients with recurrent Stage Ta or T1 tumors. Our recommendation is to use a 6-week induction course of BCG followed by three weekly BCG instillations at 3 and 6 months and every 6 months thereafter for 3 years. Chemotherapy is appropriate for instillation at the time of surgery in an attempt to reduce recurrence or as a second-line therapy for patients in whom BCG immunotherapy has failed. Newer immunologic and chemotherapeutic agents, advances in PDT, and other measures to boost the efficacy of intravesical therapy for bladder cancer demonstrate potential, but much work remains to be done in these areas. REFERENCES 1. Cohen SM, and Johansson SL: Epidemiology and etiology of bladder cancer. Urol Clin North Am 19: 421 428, 1992. 2. Ratliff TL, Gillen DP, and Catalona WJ: Requirement of thymus dependent immune response for BCG mediated antitumor activity. J Urol 137: 155 159, 1987. 3. Jansson OT, Morcos E, Brundin L, et al: The role of nitric oxide in bacillus Calmette-Guérin mediated anti-tumour effects in human bladder cancer. Br J Cancer 78: 588 592, 1998. 4. Lamm DL: Bacillus Calmette-Guérin immunotherapy for bladder cancer. J Urol 134: 40 47, 1985. 5. Herr HW, Pinsky CM, Whitmore WF Jr, et al: Experience with intravesical bacillus Calmette-Guérin therapy of superficial bladder tumors. Urology 25: 119 123, 1985. 6. Herr HW: Transurethral resection and intravesical therapy of superficial bladder tumors. Urol Clin North Am 18: 525 528, 1991. 7. Pagano F, Bassi P, Milani C, et al: Low dose BCG regimen in superficial bladder cancer therapy: is it effective? J Urol 146: 32 35, 1991. 8. Melekos MD, Chionis H, Pantazakos A, et al: Intravesical bacillus Calmette-Guérin immunoprophylaxis of superficial bladder cancer: results of a controlled prospective trial with modified treatment schedule. J Urol 149: 744 748, 1993. 9. Krege S, Giani G, Meyer R, et al: A randomized multicenter trial of adjuvant therapy in superficial bladder cancer: transurethral resection only versus transurethral resection plus mitomycin C versus transurethral resection plus bacillus Calmette-Guérin. J Urol 156: 962 966, 1996. 10. Herr HW, Laudone VP, Badalament RA, et al: Bacillus Calmette-Guérin therapy alters the progression of superficial bladder cancer. J Clin Oncol 6: 1450 1455, 1988. 11. Lamm DL: Long term results of intravesical therapy for superficial bladder cancer. Urol Clin North Am 19: 573 580, 1982. 12. De Jager R, Guinan P, Lamm D, et al: Long term complete remission in bladder carcinoma in situ with intravesical Tice bacillus Calmette Guérin overview analysis of six phase II clinical trials. Urology 38: 507 514, 1991. 13. Lamm DL, Blumenstein BA, Crawford ED, et al: A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional cell carcinoma of the bladder. N Engl J Med 325: 1205 1209, 1991. 14. Lamm DL: BCG immunotherapy for transitional-cell carcinoma in situ of the bladder. Oncology (Huntingt) 9: 947 952, 1995. 15. Orsola A, Palou J, Xavier B, et al: Primary bladder carcinoma in situ: assessment of early BCG response as a prognostic factor. Eur Urol 33: 457 463, 1998. 16. Rosenbaum RS, Park MC, and Fleischmann J: Intravesical bacille Calmette-Guérin therapy for muscle invasive bladder cancer. Urology 47: 208 211, 1996. 17. Badalament RA, Herr HW, Wong GY, et al: A prospective randomized trial of maintenance versus nonmaintenance intravesical bacillus Calmette-Guérin therapy of superficial bladder cancer. J Clin Oncol 5: 441 447, 1987. 18. Kavoussi LR, Torrence RJ, Gillen DP, et al: Results of 6 weekly intravesical bacillus Calmette-Guérin instillations on the treatment of superficial bladder tumors. J Urol 139: 935 940, 1988. 19. Lamm DL, Blumenstein B, Sarsody M, et al: Significant long-term patient benefits with BCG maintenance therapy: a South West Oncology Group study. J Urol 157: 213 216, 1997. 20. Lamm DL, Riggs DR, Shriver JS, et al: Megadose vitamins in bladder cancer: a double-blind clinical trial. J Urol 151: 21 26, 1994. 21. Lamm DL, van der Meijden APM, Morales A, et al: Incidence and treatment of complications of bacillus Calmette- Guérin intravesical therapy in superficial bladder cancer. J Urol 147: 596 600, 1992. 22. De Boer EC, Steerenberg PA, van der Meijden APM, et al: Impaired immune response by isoniazid treatment during intravesical BCG administration in the guinea pig. J Urol 148: 1577 1582, 1992. 23. DeHaven JI, Traynelis C, Riggs DR, et al: Antibiotic and steroid therapy of massive systemic bacillus Calmette-Guérin toxicity. J Urol 147: 738 742, 1992. 24. Bohle A, Schuller J, Knipper A, et al: Bacillus Calmette- Guérin treatment and vesicorenal reflux. Eur Urol 17:125 128, 1990. 25. Glashan R: A randomized controlled study of intravesical -2b-interferon in carcinoma in situ of the bladder. J Urol 144: 658 672, 1990. 26. Torti FM, Shortliffe LD, Williams RD, et al: Alpha-interferon in superficial bladder cancer: a northern California oncology group study. J Clin Oncol 6: 476 483, 1988. 27. Belldegrun AS, Franklin JR, O Donnell MA, et al: Superficial bladder cancer: the role of interferon-alpha. J Urol 159: 1793 1801, 1998. 28. Lamm DL, Morales A, Grossman HB, et al: Keyhole UROLOGY 55 (2), 2000 167

limpet hemocyanin (KLH) immunotherapy of papillary and in situ transitional cell carcinoma of the bladder. A multicenter phase I-II clinical trial. J Urol 155: A1405, 1996. 29. Jurincic CD, Engelmann U, Gasch J, et al: Immunotherapy in bladder cancer with keyhole limpet hemocyanin: a randomized study. J Urol 139: 723 726, 1988. 30. Flamm J, Bucher A, Höltl W, et al: Recurrent superficial transitional cell carcinoma of the bladder: adjuvant topical chemotherapy versus immunotherapy: a prospective randomized trial. J Urol 144: 260 263, 1990. 31. Sarosdy MF, Lowe BA, Schellhammer PF, et al: Bropirimine immunotherapy of carcinoma in situ of the bladder: results of a phase II trial. Urology 48: 21 27, 1996. 32. Lamm DL, and Griffith JG: Intravesical therapy: does it affect the natural history of bladder cancer? Semin Urol 10: 39 44, 1992. 33. Walker MC, Masstera JR, Parris CN, et al: Intravesical chemotherapy in vitro studies on the relationship between dose and cytotoxicity. Urol Res 14: 137 140, 1987. 34. Wientjes MG, Dalton JT, Badalament RA, et al: Bladder wall penetration of intravesical mitomycin C in dogs. Cancer Res 51: 4347 4354, 1991. 35. Solsona E, Iborra I, Ricos JV, et al: Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and long-term followup. J Urol 161: 1120 1123, 1999. 36. Huland H, Klöppel G, Feddersen I, et al: Comparison of different schedules of cystostatic intravesical instillations in patients with superficial bladder carcinoma: final evaluation of a prospective multicenter study with 419 patients. J Urol 144: 68 75, 1990. 37. Lamm DL: Clinical evaluation of immunotherapy. Cancer Surv 31: 99 108, 1998. 38. Kim HH, and Lee C: Intravesical mitomycin C instillation as a prophylactic treatment of superficial bladder tumor. J Urol 139: 245A, 1988. 39. Thrasher JB, and Crawford ED: Complications of intravesical chemotherapy. Urol Clin North Am 19: 529 539, 1992. 40. Zincke H, Utz DC, Taylor WF, et al: Influence of thiotepa and doxorubicin instillation at time of transurethral surgical treatment of bladder cancer on tumor recurrence: a prospective, randomized, double blind, controlled trial. J Urol 129: 505 508, 1983. 41. Kamat AM, DeHaven JI, and Lamm DL: Quinolone antibiotics: a potential adjunct to intravesical chemotherapy for bladder cancer. Urology 54: 56 61, 1999. 42. Rajala P, Liukkonen T, Raitanen M, et al: Transurethral resection with perioperative instillation on interferon-alpha or epirubicin for the prophylaxis of recurrent primary superficial bladder cancer: a prospective randomized multicenter study Finnbladder III. J Urol 161: 1133 1135, 1999. 43. Okamura K, Kinukawa T, Tsumura Y, et al, for the Nagoya University Urological Oncology Group: A randomized study of short- versus long-term intravesical epirubicin instillation for superficial bladder cancer. Eur Urol 33: 285 288, 1998. 44. Greenberg RE, Bahnson RR, Wood D, et al: Initial report on intravesical administration of N- trifluoroacetyl adriamycin-14-valerate (AD 32) to patients with refractory superficial transitional cell carcinoma of the urinary bladder. Urology 49: 471 475, 1997. 45. Bahnson R, Brosman S, Dalkin B, et al: Effectiveness of valrubicin in patients with BCG-refractory carcinoma in situ of the bladder. J Urol 161: 171, 1999. 46. Nseyo UO: Photodynamic therapy. Urol Clin North Am 19: 591 599, 1992. 47. Nseyo UO, DeHaven J, Dougherty TJ, et al: Photodynamic therapy (PDT) in the treatment of patients with resistant superficial bladder cancer: a long-term experience. J Clin Laser Med Surg 16: 61 68, 1988. 48. Oosterlinck W, Kurth KH, Schröder F, et al, and the Members of the European Organization for Research and Treatment of Cancer Genitourinary Group: A prospective European organization for research and treatment of cancer genitourinary group randomized trial comparing transurethral resection followed by a single intravesical instillation of epirubicin or water in single state Ta, T1 papillary carcinoma of the bladder. J Urol 149: 749 752, 1993. 49. Abel PD: Follow-up of patients with superficial transitional cell carcinoma of the bladder: the case for a change in policy. Br J Urol 72: 135 142, 1993. 50. Bostwick DG: Natural history of bladder cancer. J Cell Biochem 161: 31 38, 1991. 51. Messing EM, Young TB, Hunt VB, et al: Comparison of bladder cancer outcome in men undergoing hematuria home screening versus those with standard clinical presentations. Urology 45: 387 396, 1995. 52. Herr HW: Tumour progression and survival in patients with T1G3 bladder tumours: 15-year outcome. Br J Urol 80: 762 765, 1997. 53. Vicente J, Laguna MP, Duarte D, et al: Carcinoma in situ as a prognostic factor for G3pT1 bladder tumours. Br J Urol 68: 380 382, 1991. 54. Obek C, Shelfo SW, Korman HJ, et al: Intravesical therapy for transitional cell carcinoma of the bladder: the community practice. Urology 53: 82 87, 1999. 55. Lamm DL, and Torti FM: Bladder cancer, 1996. CA Cancer J Clin 46: 93 112, 1996. 56. Prout GR Jr, Koontz WW Jr, Coombs LJ, et al, for the National Bladder Cancer Collaborative Group: Long-term fate of 90 patients with superficial bladder cancer randomly assigned to receive or not to receive thiotepa. J Urol 130: 677 680, 1983. 57. Akaza H, Koiso K, Kotake T, et al, and the Japanese Urological Cancer Research Group for Adriamycin: Long term results of intravesical chemoprophylaxis of superficial bladder cancer: experience of the Japanese Urological Cancer Research Group for Adriamycin. Cancer Chemother Pharmacol 30: 15 19, 1992. 58. Kurth KH, Debruyne FJM, Senge T, et al, and the Members of the EORTC GU-Group: Adjuvant chemotherapy of superficial transitional cell carcinoma: an E.O.R.T.C. randomized trial comparing doxorubicin hydrochloride, ethoglucid, and TUR alone, in Schröder FH, and Richards B (Eds): EORTC Genitourinary Group Monograph 2, Part B: Superficial Bladder Tumors. New York, Alan R Liss, 1985, pp 135 142. 59. Pawinski A, Sylvester R, Kurth KH, et al: A combined analysis of EORTC/MRC randomized clinical trials for the prophylactic treatment of stage TaT1 bladder cancer. J Urol 156: 1934 1940, 1996. 60. Lamm DL, Riggs DR, Traynelis CL, et al: Apparent failure of current intravesical chemotherapy prophylaxis to influence the long-term course of superficial transitional cell carcinoma of the bladder. J Urol 153: 1444 1450, 1995. 61. Melekos MD, Chionis HA, Paranychianakis GS, et al: Intravesical 4 -epi-doxorubicin (epirubicin) versus bacillus Calmette-Guérin. Cancer 72: 1749 1755, 1993. 62. Cookson MS, and Sarosdy MF: Management of stage T1 superficial bladder cancer with intravesical bacillus Calmette- Guérin therapy. J Urol 148: 797 801, 1992. 63. Klein EA, Rogatko A, and Herr HW: Management of local bacillus Calmette-Guérin failures in superficial bladder cancer. J Urol 147: 601 605, 1992. 64. Okuno H, Kakehi Y, Ozdemir E, et al: Association of in vitro growth potential of urinary exfoliated cells with tumor localization and intraluminal recurrence rates of urothelial cancers. J Urol 158: 1996 1999, 1997. 168 UROLOGY 55 (2), 2000