Intravesical therapy for bladder cancer

Abstract

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 1995.1Cohen S.M Johansson S.L Epidemiology and etiology of bladder cancer.Urol Clin North Am. 1992; 19: 421-428PubMed Google Scholar 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. 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.2Ratliff T.L Gillen D.P Catalona W.J Requirement of thymus dependent immune response for BCG mediated antitumor activity.J Urol. 1987; 137: 155-159PubMed Google Scholar 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.3Jansson O.T 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. 1998; 78: 588-592Crossref PubMed Scopus (47) Google Scholar Table I summarizes six studies showing a reduction of tumor recurrence from an average of 67% in controls to 29% with BCG.4Lamm D.L Bacillus Calmette-Guérin immunotherapy for bladder cancer.J Urol. 1985; 134: 40-47Abstract Full Text PDF PubMed Google Scholar, 5Herr H.W Pinsky C.M Whitmore Jr, W.F et al.Experience with intravesical bacillus Calmette-Guérin therapy of superficial bladder tumors.Urology. 1985; 25: 119-123Abstract Full Text PDF PubMed Scopus (101) Google Scholar, 6Herr H.W Transurethral resection and intravesical therapy of superficial bladder tumors.Urol Clin North Am. 1991; 18: 525-528PubMed Google Scholar, 7Pagano F Bassi P Milani C et al.Low dose BCG regimen in superficial bladder cancer therapy is it effective?.J Urol. 1991; 146: 32-35Abstract Full Text PDF PubMed Scopus (155) Google Scholar, 8Melekos M.D 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. 1993; 149: 744-748PubMed Google Scholar, 9Krege 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. 1996; 156: 962-966Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar In Lamm’s study,4Lamm D.L Bacillus Calmette-Guérin immunotherapy for bladder cancer.J Urol. 1985; 134: 40-47Abstract Full Text PDF PubMed Google Scholar the mean time to recurrence increased from 24 to 48 months (P <0.01). Herr et al.5Herr H.W Pinsky C.M Whitmore Jr, W.F et al.Experience with intravesical bacillus Calmette-Guérin therapy of superficial bladder tumors.Urology. 1985; 25: 119-123Abstract Full Text PDF PubMed Scopus (101) Google Scholar 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).10Herr H.W Laudone V.P Badalament R.A et al.Bacillus Calmette-Guérin therapy alters the progression of superficial bladder cancer.J Clin Oncol. 1988; 6: 1450-1455Crossref PubMed Scopus (221) Google Scholar In a subsequent report with 3 years additional follow-up, cancer deaths were reduced from 37% to 12% (P <0.01).6Herr H.W Transurethral resection and intravesical therapy of superficial bladder tumors.Urol Clin North Am. 1991; 18: 525-528PubMed Google Scholar Pagano et al.7Pagano F Bassi P Milani C et al.Low dose BCG regimen in superficial bladder cancer therapy is it effective?.J Urol. 1991; 146: 32-35Abstract Full Text PDF PubMed Scopus (155) Google Scholar 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.11Lamm D.L Long term results of intravesical therapy for superficial bladder cancer.Urol Clin North Am. 1982; 19: 573-580Google ScholarTABLE IComparison of recurrence after TURBT alone vs. after BCG therapylegendKey: TURBT = transurethral resection of bladder tumor; BCG = bacille Calmette-Guérin., legendNumbers in parentheses are percentages.InvestigatorsTotal (n)TURBT AloneBCG TherapyP ValueControl (n)Recurrence (n)Treatment (n)Recurrence (n)Lamm,4Lamm D.L Bacillus Calmette-Guérin immunotherapy for bladder cancer.J Urol. 1985; 134: 40-47Abstract Full Text PDF PubMed Google Scholar 1985572714 (52)306 (20)<0.001Herr et al.,5Herr H.W Pinsky C.M Whitmore Jr, W.F et al.Experience with intravesical bacillus Calmette-Guérin therapy of superficial bladder tumors.Urology. 1985; 25: 119-123Abstract Full Text PDF PubMed Scopus (101) Google Scholar 1985864341 (95)4318 (42)<0.001Herr et al.,6Herr H.W Transurethral resection and intravesical therapy of superficial bladder tumors.Urol Clin North Am. 1991; 18: 525-528PubMed Google Scholar 1991492626 (100)238 (35)<0.001Pagano et al.,7Pagano F Bassi P Milani C et al.Low dose BCG regimen in superficial bladder cancer therapy is it effective?.J Urol. 1991; 146: 32-35Abstract Full Text PDF PubMed Scopus (155) Google Scholar 19911336352 (83)7018 (26)<0.001Melekos et al.,8Melekos M.D 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. 1993; 149: 744-748PubMed Google Scholar 1993943219 (59)6220 (32)<0.02Krege et al.,9Krege 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. 1996; 156: 962-966Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar 199622412256 (46)10226 (26)<0.01Total643313208 (67)33096 (29)legend Key: TURBT = transurethral resection of bladder tumor; BCG = bacille Calmette-Guérin.legend Numbers in parentheses are percentages. Open table in a new tab 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.12De 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. 1991; 38: 507-514Abstract Full Text PDF PubMed Scopus (70) Google Scholar With optimal BCG immunotherapy, the complete response (CR) rate can be increased to 87%.13Lamm D.L Blumenstein B.A Crawford E.D 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. 1991; 325: 1205-1209Crossref PubMed Scopus (507) Google Scholar 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).14Lamm D.L BCG immunotherapy for transitional-cell carcinoma in situ of the bladder.Oncology. 1995; 9 (Huntingt): 947-952PubMed Google Scholar Herr et al.10Herr H.W Laudone V.P Badalament R.A et al.Bacillus Calmette-Guérin therapy alters the progression of superficial bladder cancer.J Clin Oncol. 1988; 6: 1450-1455Crossref PubMed Scopus (221) Google Scholar 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 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.15Orsola A Palou J Xavier B et al.Primary bladder carcinoma in situ assessment of early BCG response as a prognostic factor.Eur Urol. 1998; 33: 457-463Crossref PubMed Scopus (28) Google Scholar 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.16Rosenbaum R.S Park M.C Fleischmann J Intravesical bacille Calmette-Guérin therapy for muscle invasive bladder cancer.Urology. 1996; 47: 208-211Abstract Full Text PDF PubMed Scopus (12) Google Scholar 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.17Badalament R.A Herr H.W Wong G.Y et al.A prospective randomized trial of maintenance versus nonmaintenance intravesical bacillus Calmette-Guérin therapy of superficial bladder cancer.J Clin Oncol. 1987; 5: 441-447Crossref PubMed Scopus (200) Google Scholar Kavoussi et al.18Kavoussi L.R Torrence R.J Gillen D.P et al.Results of 6 weekly intravesical bacillus Calmette-Guérin instillations on the treatment of superficial bladder tumors.J Urol. 1988; 139: 935-940Abstract Full Text PDF PubMed Scopus (102) Google Scholar 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.19Lamm D.L Blumenstein B Sarsody M et al.Significant long-term patient benefits with BCG maintenance therapy a South West Oncology Group study.J Urol. 1997; 157: 213-216Abstract Full Text Full Text PDF Scopus (1) Google Scholar 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, B6, 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.20Lamm D.L Riggs D.R Shriver J.S et al.Megadose vitamins in bladder cancer a double-blind clinical trial.J Urol. 1994; 151: 21-26Abstract Full Text PDF PubMed Scopus (139) Google Scholar BCG is generally well tolerated, although symptoms of cystitis do occur in up to 90% of patients.21Lamm D.L van der Meijden A.P.M Morales A et al.Incidence and treatment of complications of bacillus Calmette-Guérin intravesical therapy in superficial bladder cancer.J Urol. 1992; 147: 596-600Abstract Full Text PDF PubMed Scopus (638) Google Scholar 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.22De Boer E.C Steerenberg P.A van der Meijden A.P.M et al.Impaired immune response by isoniazid treatment during intravesical BCG administration in the guinea pig.J Urol. 1992; 148: 1577-1582PubMed Google Scholar 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.23DeHaven J.I Traynelis C Riggs D.R et al.Antibiotic and steroid therapy of massive systemic bacillus Calmette-Guérin toxicity.J Urol. 1992; 147: 738-742PubMed Google Scholar There is no evidence that BCG therapy is contraindicated in patients with vesicoureteral reflux.24Bohle A Schuller J Knipper A et al.Bacillus Calmette-Guérin treatment and vesicorenal reflux.Eur Urol. 1990; 17: 125-128PubMed Google Scholar BCG should not be given to immunocompromised patients or after a traumatic catheterization. Interferons are host-produced glycoproteins that mediate host immune responses in a dose-dependent fashion.25Glashan R A randomized controlled study of intravesical α-2b-interferon in carcinoma in situ of the bladder.J Urol. 1990; 144: 658-672Abstract Full Text PDF PubMed Scopus (141) Google Scholar Torti et al.26Torti F.M Shortliffe L.D Williams R.D et al.Alpha-interferon in superficial bladder cancer a northern California oncology group study.J Clin Oncol. 1988; 6: 476-483Crossref PubMed Scopus (134) Google Scholar 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.27Belldegrun A.S Franklin J.R O’Donnell M.A et al.Superficial bladder cancer the role of interferon-alpha.J Urol. 1998; 159: 1793-1801Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar concluded that recombinant interferon-alpha has an important role in the treatment of superficial TCC, particularly as second- line therapy after failure of BCG or chemotherapy and that it may have synergistic effects when combined with chemotherapy or BCG. Keyhole limpet hemocyanin (KLH), a highly antigenic respiratory pigment of the mollusc Megathuria crenulata, is a nonspecific immune stimulator. Lamm et al.28Lamm D.L Morales A Grossman H.B et al.Keyhole limpet hemocyanin (KLH) immunotherapy of papillary and in situ transitional cell carcinoma of the bladder. A multicenter phase I-II clinical trial.J Urol. 1996; 155: A1405Google Scholar 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.29Jurincic C.D Engelmann U Gasch J et al.Immunotherapy in bladder cancer with keyhole limpet hemocyanin a randomized study.J Urol. 1988; 139: 723-726Abstract Full Text PDF PubMed Scopus (90) Google Scholar reported that KLH (14% recurrence) was better than mitomycin (39.1% recurrence) in the prevention of recurrent superficial TCC (P <0.05). Flamm et al.30Flamm 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. 1990; 144: 260-263Abstract Full Text PDF PubMed Scopus (36) Google Scholar reported no difference in efficacy between KLH and ethoglucid. The advantage of KLH is its apparent lack of toxicity. Bropirimine is a low-molecular-weight immunomodulator with a wide spectrum of immune stimulating activity. Sarosdy et al.31Sarosdy M.F Lowe B.A Schellhammer P.F et al.Bropirimine immunotherapy of carcinoma in situ of the bladder results of a phase II trial.Urology. 1996; 48: 21-27Abstract Full Text PDF PubMed Scopus (39) Google Scholar 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 became popular in the 1960s when thiotepa was shown to reduce tumor recurrence and eliminate one third of papillary tumors.32Lamm D.L Griffith J.G Intravesical therapy does it affect the natural history of bladder cancer?.Semin Urol. 1992; 10: 39-44PubMed Google Scholar Unlike systemic chemotherapy, responses to topical chemotherapy are proportional to the drug concentration rather than the drug dose.33Walker M.C Masstera J.R Parris C.N et al.Intravesical chemotherapy in vitro studies on the relationship between dose and cytotoxicity.Urol Res. 1987; 14: 137-140Google Scholar 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.34Wientjes M.G Dalton J.T Badalament R.A et al.Bladder wall penetration of intravesical mitomycin C in dogs.Cancer Res. 1991; 51: 4347-4354PubMed Google Scholar Table II summarizes several controlled studies that show the effect of intravesical chemotherapy on recurrence in patients undergoing transurethral resection of bladder tumor.TABLE IIEffect of intravesical chemotherapy on recurrence in controlled studies of patients undergoing transurethral resection of bladder tumorlegendKey: TURBT = transurethral resection of bladder tumor; NS = not significant., legendNumbers in parentheses are percentages.InvestigatorsTotal (n)Control (TURBT)ChemotherapyDifference % RecurredP Value∗P value 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.Control (n)Recurrence (n)Treatment (n)Recurrence (n)ThiotepaBurnand et al., 1976513231 (97)1911 (58)390.001Byar and Blackar, 1977864829 (60)3818 (47)130.016Nocks et al., 1979422214 (64)2013 (65)−1NSAsahi et al., 19801345623 (41)7831 (40)1NSSchulman et al., 198220910472 (69)10562 (59)10NSKoontz et al., 1981934731 (66)4618 (39)270.02Zincke et al., 1983582820 (71)309 (30)410.002Prout et al., 1985904543 (76)4529 (64)120.05MRCI, 198536712346 (37)24497 (40)−3NSNetto et al., 1983342016 (80)146 (43)37NSHirao et al., 1992934822 (46)457 (15)310.0015Total1257573347 (61)684301 (44)17DoxorubicinNiijima et al., 198343613986 (62)297135 (45)170.05Zincke et al., 1983592820 (71)3110 (32)390.01Kurth et al., 19852177041 (59)14752 (35)240.006Rubben et al., 19882208250 (61)13877 (56)5NSAkaza et al., 198745714849 (33)30977 (25)8NSAbrams et al., 1981572825 (89)2923 (79)10NSTotal1446495271 (55)951374 (39)16Mitomycin CHuland and Otto, 1984793116 (52)485 (10)420.01Niijima et al., 198327813986 (62)13979 (57)5NSKim and Lee, 1988432218 (82)2117 (81)1NSTolley et al., 198845215794 (60)295121 (41)18.90.001Krege et al., 199623412256 (46)11230 (27)190.004Solsona et al., 1999121648 (12)576 (10)2NSAkaza et al., 198729814849 (33)15036 (24)9NSTotal1505683327 (48)822294 (36)12EpirubicinOosterlinck et al., 198339920584 (41)19456 (29)120.0152Melekos et al., 1993993219 (59)6727 (40)19NSIgawa et al., 1996753222 (69)4326 (60)9NSRaitanen et al., 1995511917 (90)3224 (75)15NSRajala et al., 19991346640 (60)6823 (35)150.001Total†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.758354182 (51)404156 (39)12legend Key: TURBT = transurethral resection of bladder tumor; NS = not significant.legend Numbers in parentheses are percentages.∗ P value 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. Open table in a new tab 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.35Solsona E Iborra I Ricos J.V 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. 1999; 161: 1120-1123Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar 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.36Huland 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. 1990; 144: 68-75PubMed Google Scholar Mitomycin C is very expensive, and controlled trials have failed to show improved efficacy when compared with other intravesical chemotherapies.37Lamm DL: Clinical evaluation of immunotherapy. Cancer Surv 31: 99–108, 1998.Google Scholar 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.38Kim H.H Lee C Intravesical mitomycin C instillation as a prophylactic treatment of superficial bladder tumor.J Urol. 1988; 139: 245AGoogle Scholar 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, 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.11Lamm D.L Long term results of intravesical therapy for superficial bladder cancer.Urol Clin North Am. 1982; 19: 573-580Google Scholar 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%.39Thrasher J.B Crawford E.D Complications of intravesical chemotherapy.Urol Clin North Am. 1992; 19: 529-539PubMed Google Scholar Recent tumor resection, extensive tumor, or concurrent cystitis can markedly increase absorption. 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,40Zincke H Utz D.C Taylor W.F 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. 1983; 129: 505-508Abstract Full Text PDF PubMed Scopus (94) Google Scholar 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.41Kamat A.M DeHaven J.I Lamm D.L Quinolone antibiotics a potential adjunct to intravesical chemotherapy for bladder cancer.Urology. 1999; 54: 56-61Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar The primary side effect seen with doxorubicin is chemical cystitis, causing symptoms of dysuria, frequency, and urgency in up to 50% of patients. Epirubcin (4′-epidoxorubicin) is an epimer of doxorubicin. A recent trial demonstrated that a single dose of epirubicin given intravesically immediately after tumor resection was safe and significantly decreased tumor recurrence from 60% in those with resection alone to 34% in those treated with epirubicin.42Rajala 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. 1999; 161: 1133-1135Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar 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.43Okamura K Kinukawa T Tsumura Y et al.Nagoya University Urological Oncology GroupA randomized study of short- versus long-term intravesical epirubicin instillation for superficial bladder cancer.Eur Urol. 1998; 33: 285-288Crossref PubMed Scopus (33) Google Scholar Epirubicin is not, at the time of writing, available in the United States, but approval for lung cancer has been sought. 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 breaking-resealing action of DNA topoisomerase II. Greenberg et al.44Greenberg R.E Bahnson R.R 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. 1997; 49: 471-475Abstract Full Text PDF PubMed Scopus (56) Google Scholar 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.45Bahnson R Brosman S Dalkin B et al.Effectiveness of valrubicin in patients with BCG-refractory carcinoma in situ of the bladder.J Urol. 1999; 161: 171Crossref Google Scholar 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. PDT involves intravenous administration of a photosensitizer such as Photofrin (sodium porfimer), which is a mixture of hematoporphyrin-derived