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AN OVERVIEW OF THE TREATMENT OF SUPERFICIAL BLADDER CANCER
SUPERFICIAL BLADDER CANCER: NEW STRATEGIES IN DIAGNOSIS AND TREATMENT
0094-0143/00 $8.00
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AN OVERVIEW OF THE TREATMENT OF SUPERFICIAL BLADDER CANCER Intravesical Chemotherapy Jose Luis F. Duque, MD, and Kevin R. Loughlin, MD
Superficial bladder cancer accounts for approximately 70% to 80% of all newly diagnosed bladder cancers. The majority of these cancers are transitional bladder tumors of various histologic grades (I to 111). Superficial tumors include carcinoma in situ (CIS), tumors confined to the epithelium (Ta), and superficial tumors that invade the lamina propria (Tl) but do not involve superficial muscle layers. The primary treatment for eradicating stages Ta and T1 bladder cancers is transurethral resection (TUR) of the Many patients with superficial bladder tumors treated with endoscopic surgery alone have recurrence or tumor progression at some point in their follow-up, and, in these patients, the need for adjuvant treatment becomes a major concern. Intravesical chemotherapy for the treatment of superficial bladder cancer was initially reported in 1900 when Herringz0described the use of silver nitrate. Studies in Europe performed initially with thiotepa showed that such drugs could eradicate residual bladder tumors and potentially decrease
the use of inlocal r e c ~ r r e n c e .68~ ~Today, , travesical chemotherapy for superficial bladder cancer has become more generally accepted. The main goals of intravesical therapy are to prevent tumor recurrence or tumor progression after TUR of the primary tumor and to treat possible residual tumors after endoscopic surgery. The identification of patients with superficial bladder tumors who are at risk for tumor recurrence and tumor progression after surgical treatment is very important in the selection of candidates for adjuvant or prophylatic use of intravesical the rap^.^, 51 Risk factors include tumor size and grade, multifocality, positive postoperative urine cytology, prostatic urethral involvement, the presence of CIS, and tumors that invade the lamina p r ~ p r i a . ~ Several antitumor agents with definitive activity against CIS or residual tumors after TUR have been developed.29The most commonly studied are thiotepa, doxorubicin (Adriamycin), mitomycin C , epirubicin, ethoglucid, and the nonchemotherapeutic drug bacille Calmette-Gu6rin (BCG). The
From the Department of Surgery, Division of Urology, Children’s Hospital (JLFD) and Brigham and Women’s Hospital, Harvard Medical School (JLFD, KRL), Boston, Massachusetts
UROLOGIC CLINICS OF NORTH AMERICA VOLUME 27 * NUMBER 1 * FEBRUARY 2000
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DUQUE & LOUGHLIN
ideal drug for intravesical therapy would be inexpensive and would have minimal systemic absorption and local toxicity while effectively preventing tumor recurrence and progression after TUR of the primary In the past decade, BCG has emerged as an important intravesical agent because of its economy and effectiveness in prophylaxis against tumor recurrence after TUR of the primary tumor, in the treatment of residual tumors, and in patients with CIS.4l Nevertheless, the toxicity and side effects of intravesical BCG therapy cannot be ignored. Dysuria and urinary frequency occur in about 90% of patients. Furthermore, approximately 24% of patients have fever, and 18% and 8% of patients have malaise and nausea, respectively?' Antituberculosis therapy is required in as many as 6% of the patients treated with BCG owing to the severity of side Some patients may not respond to intravesical BCG therapy. Alternative intravesical therapy with other drugs may be effective in these patients%and in patients with considerable side effects,although other drugs also have limitations and considerable side effects as well. This article focuses on the treatment of superficial bladder cancer with chemotherapic agents. Topics discussed include the effectiveness, side effects, advantages, and disadvantages of each drug. PRINCIPLES AND INDICATIONS
The goal of intravesical therapy varies based on the circumstances in which the drug is used. Prophylactic use after complete resection of a primary tumor in patients with identifiable risk factors for tumor recurrence is usually the most common indication for intravesical chemotherapy; 50% to 70% of patients have tumor recurrence if treated with TUR alone? Intravesical chemotherapy can reduce the incidence of tumor recurrence on a short-term basis, although long-term results have been di~appointing.3~ No evidence suggests that intravesical chemotherapy reduces the incidence of tumor progression on a longterm Other less common indications for intravesical chemotherapy include its therapeutic use for eradicating post-TUR re-
sidual tumors and as an alternative treatment when BCG is not effective or when the side effects of BCG are intolerable. Some basic principles should be followed when administering intravesical chemotherapy. Distilled water is the preferred solution for drug dilution because some studies suggest that it provides better results than saline solutions.56 To achieve satisfactory results, the drug should come in contact with the target urothelium. With the exception of Adriamycin, the drug must be absorbed by the cell to exert its cytotoxic effect Local chemotherapy probably works only against dividing cells, and repeated administrations are required to obtain a response.34A recent study involving mitomycin C and doxorubicin suggested that intensive short-term instillation plus long-term maintenance may offer advantages over less intensive regimens.59The median follow-up in that study was almost 5 years. The dose and concentration of the drug to be administered are important factors in treatment effi~acy.~ The bladder should be emptied immediately before drug instillation, and the patient should be advised to avoid excessive fluid intake to prevent dilution of the agent. The ideal bladder dwell time for chemotherapeutic agents has been controversial, and this period has been chosen empirically by most urologists. Theoretically, the longer the exposure time, the more the drug will exert cytotoxic effects; however, urine production will decrease drug concentration. pH variation may increase the degradation of some chemotherapeutic drugs, decreasing efficacy. Furthermore, a higher drug concentration facilitates diffusion through the urothelium. Another factor to be considered is the length of the interval after TUR before patients should receive intravesical chemotherapy. Several studies have examined the effect of the time interval between TUR and the start of intravesical chemotherapy. Boffiox and co-workers7 reported that patients who began treatment early (less than 2 weeks after TUR) had a longer time to recurrence when compared with patients who began intravesical therapy 2 weeks or longer after resection of the primary tumor. Another study com-
AN OVERVIEW OF THE TREATMENT OF SUPERFICIAL BLADDER CANCER
pared recurrence rates with early instillation (day of TUR) versus delayed instillation (7 to 15 days after TUR) and with short-term (6 months) versus long-term treatment (12 month^).^ Patients who had delayed instillation and short-term treatment had higher recurrence rates when compared with patients who received either early instillation or extended treatment. Early instillation plus prolonged treatment did not improve results in comparison with either protocol alone. All chemotherapic agents have inherent complications. Although higher efficacy theoretically is obtained with higher doses, higher doses are also associated with higher systemic absorption and local side effects. Urethral trauma secondary to catheterization is uncommon, but if trauma is considerable, treatment should be postponed. Because urethral catheterization in the presence of infected urine may cause systemic complications, a urinalysis should be performed before instillati~n.~~ THI OTEPA
Triethylenethiophosphoramide or thiotepa was the first intravesical chemotherapeutic agent used with relative success for treatment of superficial bladder cancer. It is an alkylating agent with a molecular weight of 189 kd that exerts its cytotoxic effect by causing cross-linkage of DNA, RNA, protein, and nucleic acids with subsequent inhibition of nucleic acid synthesis. Thiotepa is not cell cyclespecific. This agent is given intravesically in a variety of schedules to treat superficial bladder cancer or on a prophylactic basis after TUR. Doses range from 30 to 60 mg of thiotepa diluted in 30 to 60 mL of water in a concentration ranging from 0.5 to 1.0 mg/mL for each instillation. Patients are instructed to retain the drug in the bladder for 1 to 2 hours. Instillation is given weekly (total of 4 to 8 weeks), and maintenance doses are given on a monthly basis, usually for up to 1 year. Although some studies have shown that thiotepa can be effective when used as a definitive and prophylactic therapy in superficial bladder cancer, the long-term results pub-
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lished by the Medical Research Working Party on Urological Cancer (Subgroup on Superficial Bladder Cancer) are not encouragi n g 3 Thiotepa did not improve recurrence rates after TUR in comparison with TUR alone; however, the dose for each instillation used in this study was 30 mg diluted in 50 mL of saline solution (0.6 mg/mL), and maintenance doses were given at 3-month intervals. The poor results of this study could be explained by the relatively low dose of thiotepa or the maintenance schedule adopted. The concentration of the drug seems to be more important in terms of intravesical chemotherapy response than the total dose of the drug given."'' Recent data show that 60 mg of the drug diluted in 30 mL of water (2 mg/ mL) can be administered without significant systemic toxicity? A meta-analysis of nine controlled randomized trials using thiotepa with different schedules as prophylactic treatment after TUR revealed a slight decrease in tumor recurrence after drug instillation when compared with TUR alone (Table 1). Five of nine studies showed some benefit (up to 41%), whereas four studies showed no benefit in subjects receiving intravesical thiotepa when compared with controls. The most significant complication of intravesical thiotepa is myelosuppression, which occurs in as many as 20% of the patients.62Leukopenia occurs in 9% to 54% of the patients and thrombocytopenia in 3% to 31%." Systemic absorption occurs owing to the small molecular weight of thiotepa. In general, approximately one third of the drug is absorbed through the urothelium.25Lunglmayr and found that, at a concentration of 1 mg/mL, 19%of the instilled thiotepa was absorbed by the urothelium. Irritative voiding symptoms occur in 12% to 69% of patients. Deaths as a result of treatment are rare, but a few cases have been reportedSz1 ADRlAMYClN Adriamycin (doxorubicin), an anthracycline antibiotic, acts as an antineoplastic drug by binding to DNA base pairs, interrupting DNA replication and transcription, and inhib-
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Table 1. RESULTS OF THIOTEPA PROPHYLACTIC ADMINISTRATION IN 9 CONTROLLED CLINICAL TRIALS IN TERMS OF TUMOR RECURRENCE
Study
Recurrence in Controls (TUR alone) (%)
Recurrence in TUR Thiotepa Group ("YO)
Difference
97 60 64 41 69 66
58 47 65 40 59 39 30 64 40
39* 13* -1 1 10 27* 41, 12* -3
Burnand et all0 Byar and Blackar" Nocks et a14s Asahi et al' Schulman et a1% Koontz et a127 Zincke et a172 Prout et al"' Medical Research Council4"
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76 37
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("w
"Differences considered statistically significant (P50.05). Data /rotti Riggs DR, Traynelis CL, et al: Apparent failure of current intravesical chemotherapy prophylaxis to influence the long-term cause of superficial transitional cell carcinoma of the bladder. J Urol 153:1444, 1995; with permission.
iting protein synthesis. Its most toxic effect is seen in the S phase of the cell cycle, although the drug is classified as non-cell cycle phasespecific. Doxorubicin has been indicated mainly in the prophylactic treatment of patients after TUR. Administered doses range from 30 to 100 mg5usually in a concentration of 1 mg/mL (0.5 to 2.0 mg/mL). Schedules are variable, usually ranging from weekly to every 3-week administration. Bladder dwell time is usually 1 to 2 hours. Maintenance schedules are variable; monthly administrations for up to 2 years have been de~cribed.'~ Although a maintenance scheme is widely accepted by most urologists, FlammI5 found that long-term maintenance was not better than short-term treatment (6 weeks with one instillation per week). Neoadjuvant intravesical chemotherapy offers no benefit in terms of tumor r e c ~ r r e n c e . ~ ~ The efficacy of Adriamycin for prophylaxis after TUR of a primary tumor has been reported in controlled series as shown in Table
2. Four of six studies demonstrated a significant advantage of Adriamycin administration in terms of tumor recurrence. Although it is clear that doxorubicin can decrease tumor recurrence, series with long-term follow-up have failed to show any improvement in regard to tumor progression in either stage or survival.31Recently a group from Japan has suggested that the intravesical instillation of Adriamycin plus verapamil can offer advantages in terms of tumor recurrence after TUR in comparison with Adriamycin alone with a median follow-up of 38.5 months.42Longer follow-up is needed to confirm this result. Systemic side effects and toxicity of Adriamycin are uncommon owing to its high molecular weight (580 kd), causing only minimal absorption of the drug into the circulation. Systemic reactions are seen in 1.2% to 5.1% of the patients64;however, local side effects are relatively common. Chemical cystitis as defined by dysuria and urinary frequency is the most common side effect and may occur in
Table 2. TUMOR RECURRENCE IN PATIENTS TREATED WITH ADJUVANT DOXORUBICIN (POST-TUR) IN CONTROLLED SERIES Recurrence in Controls (TUR alone) Study
("/.I
Niijima et aP4 Zincke et a172 Rubben et alSs Akaza et al' Kurth et a P Ali-el-Dein et a12
62 71 61 33 71 37
'Differences considered significant.
Recurrence in TUR + Doxorubicin Group (%) 45 32 56 25 52 66
Difference
("4 17* 39* 5 8 19, 29'
AN OVERVIEW OF THE TREATMENT OF SUPERFICIAL BLADDER CANCER
4% to 56% of patients.&Hematuria occurs in 14% to 41% of patients. Other less common reactions with intravesical Adriamycin include fever, gastrointestinal effects, and, rarely, allergic reactions. Reduced bladder capacity was reported in 16% of patients in one s t ~ d y . Usually, ~" symptoms related to intravesical Adriamycin are relieved with treatment interruption, and sequelae are rarely seen.
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rence and length of disease-free interval. With a median follow-up of 7 years, the same group reported a slight advantage of five instillations over a single instillation, but no definitive conclusions could be drawn. One and five instillations resulted in decreased recurrence rates in comparison with controls; however, no benefit was seen regarding progression rates with either therapy.& Another group has suggested that 40 mg of mitomycin given for 6 months is superior to 30 mg for 12 months.67Solsona and coMlTOMYClN C w o r k e r ~reported ~~ that a single instillation of 30 mg of mitomycin after TUR in patients with low-risk superficial bladder cancer ofMitomycin C is an alkylating agent with a fered advantages when compared with no molecular weight of 334 kd. Its mechanism of treatment only on a short-term basis. Solsona action has not been totally clarified, although and colleagues suggested that cell implantasome evidence suggests that it acts by bindtion as a mechanism of early tumor recuring to DNA, resulting in synthesis inhibition rence could be controlled with a single dose and strand breakage. Mitomycin C is most of mitomycin after TUR in patients with lowsensitive in the late G, and early S phase, but overall it is considered cell cycle-non~pecific.~ risk superficial bladder cancer. This assumption was based on the fact that patients who Instillation schedules are variable. Doses received mitomycin after TUR had signifirange from 20 to 60 mg diluted in water in a cantly more late than early recurrences, and concentration ranging from 0.5 to 2.0 mg/mL, there was no relationship between early and with bladder dwell time ranging from 1 to 2 late recurrences among the controls (TUR hours. Response rates seem to increase with only). The efficacy of the prophylactic use of increasing doses?' The drug is usually adminmitomycin in other controlled trials is shown istered weekly for a period of 8 weeks, folin Table 3. lowed by monthly maintenance doses for up Because of its high molecular weight, abto 1 year.22Although the role of maintenance sorption of mitomycin in the systemic circulatherapy is controversial, in a randomized protion is low, and, systemic reactions are not spective controlled trial, Tolley and co-workcommon. Allergic reactions occur in 3% to e r analyzed ~ ~ ~the prophylactic role of a single dose of mitomycin after TUR (40 mg) com19% of patients. Contact dermatitis is seen in pared with five instillations over a 1-year peas many as 12%, and leukopenia and thromriod. They concluded that repeated instillabocytopenia are uncommon.64Reduced bladtions of 40 mg of intravesical mitomycin der capacity is not frequent but has been offered advantages in terms of tumor recurnoted by some researchers. The most comTable 3. EFFICACY OF PROPHYLACTIC MlTOMYClN IN CONTROLLED SERIES Recurrence in Controls (TUR only) Study Huland and Otto" Niijima et a P Kim and Lee" Rubben et als4 Akaza et all Krege et aI2" Tolley et alM 'Differences considered significant.
("/.I 50 62 82 42 33 46 54
Recurrence in Mitomycin TUR Group (%)
+
7 57 81
35 24 27 32
Difference
("A) 43* 5 1 7 9 19* 22'
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mon local side effects are dysuria and urinary frequency, occuring in as many as 41% of patients." EPlRUBlClN
Epirubicin (4'-epidoxorubicin)is an anthracycline derivate of doxorubicin. The mechanism of action is similar to that of doxorubicin (DNA synthesis inhibition with further protein synthesis inhibition), with a more favorable toxicity p r ~ f i l eDoses .~ range from 50 to 80 mg/mL at a concentration of 1.0 to 1.6 mL. Instillation is usually initiated 1 to 2 weeks after TUR and is performed weekly for a total of 8 weeks and then monthly to complete 1 year of treatment.2Patients are instructed to hold the drug in the bladder for 1 to 2 hours after administration. In an initial study car59% of ried out by Kurth and ~o-workers,~~ patients had a complete response, and, with a mean follow-up of 35 months, 62% of the patients with an initial complete response were alive without recurrences. One third of the patients analyzed had a durable complete response. Prospective controlled series have shown that epirubicin can significantly decrease tumor recurrence even when instilled in a single-dose manner after TUR.48Although an initial study performed in Japan suggested that epirubicin had efficacy similar to that of Adriamycin>l a more recent study comparing the efficacy of epirubicin and doxorubicin has shown that epirubicin is, in fact, more effective than doxorubicin in terms of tumor recurrence after TUR. Epirubicin was also associated with lower toxicity.* In this controlled randomized study, two doses of epirubicin were used-50 and 80 mg. Although there were no significant differences in terms of simple recurrence rates, the recurrent rates per 100 patient-months (defined as the total number of positive cystoscopic studies irrespective of the number of tumors divided by the total months of follow-up from the date of the last TUR at study entry until the final cystoscopic examination multiplied by 100) were statistically different between the two groups. Side effects were higher in the doxorubicin group than in the 50- and 80mg epirubicin groups. Systemic toxicity of
epirubicin was not observed, although an allergic reaction rate of l % has been repeated in other ~eries.4~ The most common side effects are mild urinary symptoms. A contracted bladder occurs in less than 1%of patients? ETHOGLUCID
Ethoglucid (triethylene glycol diglycidyl ether) is a podophyllin derivative with a molecular weight of 262 kd. Its mechanism of action is similar to that of an alkylating agent.5 The dose used is usually about 1 g of the drug diluted in 100 mL of sterile water (lYo ~ o l u t i o n ) . ~Initial ' instillation is performed 1 to 2 weeks after TUR, followed by four to ten instillations performed on a weekly basis. Maintenance doses are given monthly for up to 1 year. Bladder dwell time is 1 hour. Recent data from a controlled randomized trial with a long follow-up suggest that patients undergoing prophylactic intravesical ethoglucid therapy have a prolonged time to first recurrence and a decrease in recurrence rates in comparison with patients treated with TUR alone. Ethoglucid did not influence tumor progression to muscle invasive disease and survival in comparison with TUR alone.3I Because of its high molecular weight, ethoglucid is poorly absorbed, and systemic side effects are rare. A recent series reported fever and allergic skin reaction in approximately 4% of patient^.^^ No myelosupression was seen in that study; however, a few cases have been reported in other series. Local side effects such as urgency and frequency are reported in 3% to 59%of studies." OTHER AGENTS
Mitoxantrone is a synthetic, intercalating, anthraquinone-based agent related structurally and in its mode of action to doxorubicin.43In a prospective randomized controlled trial, patients who received mitoxantrone did not have improved tumor recurrence rates in comparison with patients who underwent TUR only,I6 although the time to recurrence
AN OVERVIEW OF THE TREATMENT OF SUPERFICIAL BLADDER CANCER
was longer in patients who received intravesical chemotherapy. No advantage in terms of tumor progression was noted. Chemical cystitis occurred in 11%of patients. Severe reactions are rare.64 N-trifluoroacetyladriamycin-14-valerate (AD 32) is an anthracycline that has proved to be less toxic and therapeutically superior to doxorubicin in animal models. Recent data suggest that it may be beneficial in the treatment of superficial bladder cancer, but no prospective randomized controlled trial has proved its efficacy in decreasing tumor recurrence and progression after treatment of a primary 1esi0n.I~ COMBINED INTRAVESICAL CHEMOTHERAPY
Because no drug available for intravesical chemotherapy is 100%effective in eradicating bladder tumors or in preventing tumor recurrence and because tumor progression seems to occur regardless of whether patients receive prophylactic local chemotherapy, a combination of two or more drugs has been investigated. The results of three studies combining mitomycin and Adriamycin have been published in the last 7 years. Isaka and co-workersZ4treated 40 patients with superficial bladder cancer with a combination of 20 mg of mitomycin on day 1 and 30 mg of doxorubicin on day 2 each week for 5 consecutive weeks (20 patients received prophylaxis after TUR and 20 were treated for multiple recurrences). A complete response was seen in 45% of the patients treated for multiple recurrences. Of patients receiving prophylactic instillation after TUR of primary multiple or high-grade tumors, 66%were free of recurrence with a mean follow-up of 14 months. Fukui and co-worker~'~ treated 101 patients with superficial bladder cancer using a similar schedule, the same dose of mitomycin, and 40 mg of doxorubicin. Fifty-one patients had a complete response (23 patients with stage Tis and 28 with stage Ta or T1 disease). These patients were randomized into two arms: (1) nonmaintenance and (2) monthly maintenance for 1 year. Patients with stage
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Tis tumors did significantly better with a maintenance schedule in terms of tumor recurrence rates, whereas maintenance therapy did not improve recurrence rates significantly in patients with papillary tumors. Mean follow-up ranged from 7 to 44 months. Half of the patients had significant local side effects (voiding symptoms). Sekine and co-workers60treated 43 patients with CIS with a combination of 20 mg of mitomycin on day 1 and 40 mg of doxorubicin on day 2 once a week for 5 weeks. A complete response was achieved in 74% of the patients after initial therapy. Among the responders, 41% had a local recurrence. Maintenance therapy with either mitomycin plus doxorubicin or mitomycin alone did not improve recurrence rates when compared with no maintenance therapy. The median followup was almost 5 years. COMBINED INTRAVESICAL CHEMOTHERAPYAND IMMUNOTHERAPY
Combined chemotherapy and immunotherapy may have a synergistic antitumor effect because their mechanisms of action are different. Potential benefits in terms of tumor recurrence and progression could be achieved with combined therapy. A group from Finland53studied the combination of intravesical BCG and mitomycin for CIS. Patients were randomized in two arms. One group received only mitomycin (20 to 40 mg), and the second group received a combination of mitomycin and BCG (75 mg). Combined therapy was associated with better results when compared with mitomycin alone in terms of complete response, disease-free interval, and tumor recurrence. Mean follow-up was 33 months. The same group from Finland52performed a subsequent study analyzing 188 patients with rapidly recurring stage Ta or T1 tumor. These patients were randomly treated with the same doses of mitomycin or mitomycin plus BCG. N o difference was observed between the groups in terms of tumor recurrence and disease-free interval with a mean follow-up of 34 months. Witjes and c o - w ~ r k e r shave ~ ~ reported the
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DUQUE & LOUGHLIN
results of a randomized phase 111 protocol comparing ten administrations of mitomycin with four administrations of mitomycin plus six of BCG, all performed on a weekly basis following TUR in patients with moderate and high-risk superficial bladder cancer. Patients with CIS were included in this study. No significant differences were found between the two groups in terms of tumor recurrence, tumor progression, or systemic toxicity. COMPARATIVE SERIES
No clear evidence suggests that any drug is superior to another in terms of tumor recurrence, progression, and survival.33One recent prospective randomized study2 suggested that epirubicin was superior to doxorubicin in terms of recurrence and toxicity. A group from Portugal reported equal efficacy when comparing chemoprophylactic use of mitomycin with epirubicin in a noncontrolled randomized trial.I2Several comparisons between chemotherapy (mitomycin) and immunotherapy (BCG) have been made in recent years, and the results are contr~versial.~~ A randomized clinical trial conducted by Krege and coworkersZ6showed that the risk of recurrence was the same with BCG versus mitomycin therapy. In a randomized trial comparing the prophylactic use of mitomycin, Tice BCG, and RIVM-BCG, Vegt and c o - w ~ r k e r sshowed ~~ that mitomycin and RIVM-BCG were equally effective in terms of tumor recurrence, and that mitomycin was more effective than Tice BCG. Lundholm and c o - ~ o r k e r sfound ~ ~ that BCG was superior for recurrence prophylaxis (patients in the BCG group had fewer recurrences and a significantly longer time to treatment failure when compared with patients treated with mitomycin). Witjes and co-workem7’randomized 342 patients to receive BCG or mitomycin after TUR. With a median follow-up of 7 years, they concluded that the efficacy of both treatments was the same in regard to tumor recurrence; however, mitomycin was more effective than BCG in terms of tumor progression in patients without CIS. Malmstrom and c o - ~ o r k e r shave ~ ~ reported their updated data (from the Lundholm study3s) comparing mitomycin with BCG
with a median follow-up of 64 months. BCG was superior to mitomycin for recurrence prophylaxis, but no difference was found regarding tumor progression and survival. INTRAVESICAL CHEMOTHERAPY IN THE TWENTY-FIRST CENTURY
Research efforts have focused on defining the mechanism of action of the chemotherapic agents and factors influencing drug activity in an attempt to increase the efficacy of these agents. In vitro studies suggest that interferon-a may increase the efficacy of doxorubicin and mitomycin by decreasing cell proliferation in human bladder carcinoma cell lines.j6 Recently obtained data support the assumption that there is a linear correlation between drug uptake in the bladder tissues and drug concentration in the urine.ls Future prospective studies using higher drug concentration instead of higher total dose may increase the efficacy of intravesical chemotherapy. Pharmacokinetic studies have shown that electromotive delivery of mitomycin enhances the penetration of the drug into viable bladder wall Preliminary clinical data comparing electromotive administration of mitomycin with standard administration of the drug show similar complete response rates in the two groups but suggest that, among responders, electromotive administration may offer some advantage in terms of tumor recurrence on a short-term b a s k 9 Absorption enhancers such as dimethyl sulfoxide may provide rationale for future clinical trials involving intravesical chemotherapy for superficial bladder cancers. Tumor histology is correlated with tumor sensitivity to mitomycin. Well-differentiated bladder tumors have a greater sensitivity to mitomycin than undifferentiated invasive tum o r ~ These . ~ ~ data confirm the importance of patient selection in the success of drug treatment. Recent experimental data suggest that photodynamic therapy with 5-aminolevulinic acid can enhance the effect of mitomycin on a bladder cancer cell line, suggesting a possible role in combined therapy.I3 Intravesical chemotherapy can provide a decrease in tumor recurrence rates on a short-
AN OVERVIEW OF THE TREATMENT OF SUPERFICIAL BLADDER CANCER
and long-term basis.49A prolonged diseasefree interval is achieved with adjuvant intravesical chemotherapy. BCG seems to be the best available prophylactic treatment for superficial bladder cancer, although chemotherapy may provide similar results in selected patients. Studies with long-term follow-up show that tumor progression and survival are not affected by post-TUR intravesical chemotherapy. Further studies focusing on risk factors and tumor biology will be helpful in the selection of ideal patients for intravesical Chemotherapy. References I . Akaza H, Isaka 5, Koiso K, et al: Comparative analysis of short-term and long-term prophylactic intravesical chemotherapy of superficial bladder cancer: Prospective, randomized, controlled studies of the Japanese Urological Cancer Research Group. Cancer Chemother Pharmacol2O(suppl):91, 1987 2. Ali-cl-Dein B, el-Baz M, Aly AN, et al: Intravesical epirubicin versus doxorubicin for superficial bladder tumors (stages pTa and pT1): A randomized prospective study. J Urol 158:68, 1997 3. Anonymous: The effect of intravesical thiotepa on tumor recurrence after endoscopic treatment of newly diagnosed superficial bladder cancer: A further report with long-term follow-up of a Medical Research Council Working Party on Urological Cancer, Subgroup on Superficial Bladder Cancer. Br J Urol 73:632, 1994 4. Asahi T, Matsumura Y, Tanahashi T, et al: The effects of intravesical instillation of thio-tepa on the recurrence rate of bladder tumors. Acta Med Okayama 34:43, 1980 5. Badalament RA, Farah RN: Treatment of superficial bladder cancer with intravesical chemotherapy. Semin Surg Oncol 13335, 1997 6 . Batts CN: Adjuvant intravesical therapy for superficial bladder cancer. Ann Pharmacother 261270, 1992 7. Bouffioux CH, Denis L, Oosterlinck W, et al: Adjuvant chemotherapy of recurrent superficial transitional cell carcinoma: Results of a European Organization for Research on Treatment of Cancer, randomized trial comparing intravesical instillation of thiotepa, doxorubicin and cisplatin. J Urol I48:297, 1992 8. Bouffioux CH, Kurth KH, Bono A, et al, and the members of the European Organization for Research and Treatment of Cancer Genitourinary Group: Intravesical adjuvant chemotherapy for superficial transitional cell bladder carcinoma: Results of 2 European Organization for Research and Treatment of Cancer randomized trials with mitomycin C and doxorubicin comparing early versus delayed instillations and short-term versus -long-term treatment. J Urol 153934, 1995 9. Brausi M, Campo B, Pizzocaro G, et al: Intravesical electromotive administration of drugs for treatment of superficial bladder cancer: A comparative phase I1 study. Urology 51:506, 1998
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10. Bumand KG, Boyd PJR, Mayo ME, et a]: Single dose intravesical thiotepa as a n adjuvant to cystodiathermy in the treatment of transitional cell bladder carcinoma. Br J Urol 48:55, 1976 11. Byar D, Blackard C: Comparisons of placebo, pyridoxine, and topical thiotepa in preventing recurrence of stage I bladder cancer. Urology 10556, 1977 12. Da Silva FC, Ferrito F, Brandao T, et al: 4’-Epidoxombicin versus mitomycin C intravesical chemoprophylaxis of superficial bladder cancer. Eur Urol 21:42, 1992 13. Datta SN, Allman R, Loh C, et al: Effect of photodynamic therapy in combination with mitomycin C on a mitomycin-resistant bladder cancer cell line. Br J Cancer 76312, 1997 14. Di Stasi SM, Vespasiani G, Giannantoni A, et aI: Electromotive delivery of mitomycin C into human bladder wall. Cancer Res 57875, 1997 15. Flamm J: Long-term versus short-term doxorubicin hydrochloride instillation after transurethral resection of superficial bladder cancer. Eur Urol 17119, 1990 16. Flamm 1, Donner G, Oberleitner S, et al: Adjuvant intravesical mitoxantrone after transurethral resection of primary superficial transitional cell carcinoma of the bladder: A prospective randomized study. Eur J Cancer 31A143, 1995 7. Fukui I, Kihara K, Sekine H, et al: Intravesical combination chemotherapy with mitomycin C and doxorubicin for superficial bladder cancer: A randomized trial of maintenance versus no maintenance following a complete response. Cancer Chemother Pharmacol 3O(suppl):37, 1992 8. Gao X, Au JL, Badalament RA, et al: Bladder tissue uptake of mitomycin C during intravesical therapy is linear with drug concentration in urine. Clin Cancer Res 4:139, 1998 19. Greenberg RE, Bahnson RR, Wood D, et al: Initial report on intravesical administration of N-trifluoroacetyladriamycin-14-valerate(AD32) to patients with refractory superficial transitional cell carcinoma of the urinary bladder. Urology 49:471, 1997 20. Herring HT: The treatment of vesical papilloma by injections. BMJ 23398, 1903 21. Hollister D Jr, Coleman M Hematologic effects of intravesicular thiotepa therapy for bladder carcinoma. JAMA 244:2065, 1980 22. Huben RP: Intravesical chemotherapy versus immunotherapy for superficial bladder cancer. Semin Urol Oncol 14:17, 1996 23. Huland H, Otto U Mitomycin instillation to prevent recurrence of superficial bladder carcinoma: Results of a controlled prospective study in 58 patients. Eur Urol 9:84, 1983 24. Isaka S, Okano T, Abe K, et al: Sequential instillation therapy with mitomycin C and adriamycin for superficial bladder cancer. Cancer Chemother Pharmacol 3O(suppl):41, 1992 25. Jones HC, Swinney J: Thiotepa in the treatment of tumors of the bladder. Lancet 2615, 1961 26. Kim HH, Lee C Intravesical mitomycin C instillation as a prophylactic treatment of superficial bladder tumor. J Urol 141:1337, 1989 27. Koontz WW Jr, Prout GR Jr, Smith W, et al: The use of intravesical thio-tepa in the management of noninvasive carcinoma of the bladder. J Urol 125:307, 1981 28. Krege S, Giani G, Meyer R, et al: A randomized multicenter trial of adjuvant therapy in superficial
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bladder cancer: Transurethral resection only versus transurethral resection plus mitomycin C versus transurethral resection plus bacillus Calmette-Guerin. J Urol 156:962, 1996 Kurth KH: Intravesical chemotherapy for superficial bladder tumors category Ta/T1: Who should be treated and how? Semin Urol Oncol 14:30, 1996 Kurth KH, Schroeder FH, Tunn U, et al: Adjuvant chemotherapy of superficial transitional cell carcinoma: Preliminary results of a European Organization for Research on Treatment of Cancer randomized trial comparing doxorubicin hydrochloride, ethoglucid and transurethral resection alone. J Urol 132:258, 1984 Kurth K, Tunn U, Ay R, et al: Adjuvant chemotherapy for superficial transitional cell bladder carcinoma: Long-term results of a European Organization for Research and Treatment of Cancer randomized trial comparing doxorubicin, ethoglucid and transurethral resection alone. J Urol 158:378, 1997 Kurth K, Vijgh WJ, ten Kate F, et al: Phase 1/ 2 study of intravesical epirubicin in patients with carcinoma in situ of the bladder. J Urol 146:1508, 1991 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, 1995 Lum BL, Torti FM: Adjuvant intravesicular pharmacotherapy for superficial bladder cancer. J Natl Cancer lnst 83:682, 1988 Lundholm C, Norlen BJ, Ekman P, et al: A randomized prospective study comparing long-term intravesical instillations of mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma. J Urol 156372, 1996 Lunglmayr G, Czech K: Absorption studies on intraluminal thiotepa for topical cytostatic treatment of low-stage bladder tumors. J Urol 10672, 1971 Malmstrom PU, Wijkstrom H, Lundholm C, et al: 5Year follow-up of a randomized prospective study comparing mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma: Swedish-Norwegian Bladder Cancer Study Group. J Urol 1612124, 1999 Masters JR, McDermott BJ, Harland S, et al: Thiotepa pharmacokinetics during intravesical chemotherapy: The influence of dose and volume of instillate on systemic uptake and dose rate to the tumor. Cancer Chemother Pharmacol38:59, 1996 Matsumura Y, Akaza H, Isaka S, et al: The 4th study of prophylactic intravesical chemotherapy with adriamycin in the treatment of superficial bladder cancer: The experience of the Japanese Urological Cancer Research Group for adriamycin. Cancer Chemother Pharmacol3O(suppl):lO, 1992 Medical Research Council Working Party on Urological Cancer, London: The effect of intravesical thiotepa on the recurrence rate of newly diagnosed superficial bladder cancer: An h4RC study. Br J Urol57680,1985 Messing EM, Catalona W: Urothelial tumors of the urinary tract. In Walsh PC, Retik AB, Vaughan ED Jr, et a1 (eds): Campbell’s Urology, ed 7. Philadelphia, WB Saunders, 1998, vol3, pp 2327-2410 Naito S, Kotoh S, Omoto T, et al: Prophylactic intravesical instillation chemotherapy against recurrence after a transurethral resection of superficial bladder cancer: A randomized controlled trial of doxorubicin plus verapamil versus doxorubicin alone.
43. 44.
45.
46.
47.
48.
49.
50.
51. 52.
53.
54.
55.
56. 57.
The Kyushu University Urological Oncology Group. Cancer Chemother Pharmacol42:367, 1998 Namasivayam S, Whelan P: Intravesical mitoxantrone in recurrent superficial bladder cancer: A phase 11 study. Br J Urol 75:740, 1995 Niijima T, Koiso K, Akaza H: Randomized clinical trial on chemoprophylaxis of recurrence in cases of superficial bladder cancer. Cancer Chemother Pharmacol ll(suppl):579, 1983 Nocks BN, Nieh PT, Prout GR Jr: A longitudinal study of patients with superficial bladder carcinoma successfully treated with weekly intravesical thiotepa. J Urol 122:27, 1979 Okamoto E, Kinne RK, Sokeland J: Interferons modify in vitro proliferation of human bladder transitional cell carcinoma in the presence of doxorubicin and mitomycin C. J Urol 156:1492, 1996 Oosterlinck W, Kurth KH, Schroeder F, et al: TUR only versus epirubicin in single primary or recurrent Ta, T1 bladder tumors: EORTC study 30863 [abstract]. In Programs and Abstracts of the 22nd Congress, Societe Internationale d’urologie. Sevilla, Spain, 1991, p 127 Oosterlinck W, Kurth KH, Schroder F, et al: 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 stage Ta, TI papillary carcinoma of the bladder. J Urol 149:749, 1993 Pawinski A, Sylvester R, Kurth KH, et al: A combined analysis of European Organization for Research and Treatment of Cancer, and Medical Research Council Randomized Clinical Trials for the Prophylactic Treatment of Stage TaTl Bladder Cancer. J Urol 1561934, 1996 Prout GR Jr, Koontz WW Jr, Coombs LJ, et al, for the National Bladder Cancer Collaborative Group A Long-term fate of 90 patients with superficial bladder cancer randomly assigned to receive or not to receive thiotepa. J Urol 130677, 1983 Richie JP: Intravesical chemotherapy: Treatment selection, techniques, and results. Urol Clin North Am 19:521, 1992 Rintala E, Jauhiainen K, Kaasinen E, et al: Alternating mitomycin C and bacillus Calmette-Guerin instillation prophylaxis for recurrent papillary (stages Ta to TI) superficial bladder cancer: Finnbladder Group. J Urol 156:56, 1996 Rintala E, Jauhiainen K, Rajala P, et al: Alternating mitomycin C and bacillus Calmette-Guerin instillation therapy for carcinoma in situ of the bladder: The Finnbladder Group. J Urol 1542050, 1995 Rubben H, Graf-Dobberstein C, Ostwald R, et al: Prospective randomized study of adjuvant therapy after complete resection of superficial bladder cancer: Mitomycin C vs BCG Connaught vs TUR alone. In deKernion JB, Mazema E (eds): Immunotherapy of Urological Tumors. New York, Churchill Livingstone, 1990, pp 27-36 Rubben H, Lutzeyer W, Fischer N, et al, and Members of the Registry for Urinary Tract Tumors: Natural history and treatment of low and high risk superficial bladder tumors. J Urol 139283, 1988 Sarosdy MF: Principles of intravesical chemotherapy and immunotherapy. Urol Clin North Am 19509, 1992 Schmittgen TD, Weaver JM, Badalament RA, et al: Correlation of human bladder tumor histoculture
AN OVERVIEW OF THE TREATMENT OF SUPERFICIAL BLADDER CANCER
58.
59.
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62. 63.
64. 65.
proliferation and sensitivity to mitomycin C with tumor pathobiology. J Urol 1521632, 1994 Schulman CC, Robinson M, Denis L, et al: Prophylactic chemotherapy of superficial transitional cell bladder carcinoma: An EORTC randomized trial comparing thiotepa, an epipodophyllotoxin (VM26) and TUR alone. Eur Urol 8:207, 1982 Schwaibold H, Pichlmeier U, Klingenberger HJ, et al: Long-term follow-up of cytostatic intravesical instillation in patients with superficial bladder carcinoma: Is short-term, intensive instillation better than maintenance therapy? Eur Urol 31:153, 1997 Sekine H, Fukui I, Yamada T, et al: Intravesical mitomycin C and doxorubicin sequential therapy for carcinoma in situ of the bladder: A longer follow-up result. J Urol 151:27, 1994 Shuin T, Kubota Y, Noguchi S, et al: A phase I1 study of prophylactic intravesical chemotherapy with 4‘-Epirubicin in recurrent superficial bladder cancer: Comparison of 4’-Epirubicin and Adriamycin. Cancer Chemother Pharmacol35(suppl):52, 1994 Soloway MS, Ford KS: Thiotepa-induced myelosuppression: A review of 670 bladder instillations. J Urol 130889, 1983 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 follow-up. J Urol 161:1120, 1999 Thrasher JB, Crawford ED: Complications of intravesical chemotherapy. Urol Clin North Am 19:529, 1992 Tolley DA, Hargreave TB, Smith PH, et al: Effect of intravesical mitomycin C on recurrence of newly diagnosed superficial bladder cancer: Interim report
66.
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68. 69.
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from the Medical Research Council Subgroup on Superficial Cancer (Urological Cancer Working Party). BMJ 296:1759, 1988 Tolley DA, Parmar MK, Grigor KM, et al: The effect of intravesical mitomycin on recurrence of newly diagnosed superficial bladder cancer: A further report with 7 years of follow-up. J Urol 155:1233, 1996 Vecchioli S C Mitomycin-C 30 mg for 12 months versus mitomicin-C 40 mg for 6 months in the prevention of superficial bladder carcinoma Gl-G2. Minerva Urol Nefrol 48:203, 1996 Veenema RJ, Dean AL Jr, Uson AC, et al: Thiotepa bladder instillations: Therapy and prophylaxis for superficial bladder tumors. J Urol 101:711, 1969 Vegt PD, Witjes JA, Witjes WP, et al: A randomized study of intravesical mitomycin C, bacillus CalmetteGuerin Tice and bacillus Calmette-Guerin RIVM treatment in pTa-pT1 papillary carcinoma and carcinoma in situ of the bladder. J Urol 153929, 1995 Witjes JA, Caris CT,Mungan NA, et al: Results of a randomized phase 111 trial of sequential intravesical therapy with mitomycin C and bacillus CalmetteGuerin versus mitomycin alone in patients with superficial bladder cancer. J Urol 160:1668, 1998 Witjes JA, Meijden APM, Collette L, et al: Long-term follow-up of an EORTC randomized prospective trial comparing intravesical bacille Calmette-Guerin RIVM and mitomycin C in superficial bladder cancer. Urology 52403, 1998 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, 1983 Address reprint requests to
Kevin R. Loughlin, MD Brigham and Women’s Hospital 45 Francis Street Boston, MA 02115
0094-0143/00 $8.00
+ .OO
AN OVERVIEW OF THE TREATMENT OF SUPERFICIAL BLADDER CANCER Intravesical Chemotherapy Jose Luis F. Duque, MD, and Kevin R. Loughlin, MD
Superficial bladder cancer accounts for approximately 70% to 80% of all newly diagnosed bladder cancers. The majority of these cancers are transitional bladder tumors of various histologic grades (I to 111). Superficial tumors include carcinoma in situ (CIS), tumors confined to the epithelium (Ta), and superficial tumors that invade the lamina propria (Tl) but do not involve superficial muscle layers. The primary treatment for eradicating stages Ta and T1 bladder cancers is transurethral resection (TUR) of the Many patients with superficial bladder tumors treated with endoscopic surgery alone have recurrence or tumor progression at some point in their follow-up, and, in these patients, the need for adjuvant treatment becomes a major concern. Intravesical chemotherapy for the treatment of superficial bladder cancer was initially reported in 1900 when Herringz0described the use of silver nitrate. Studies in Europe performed initially with thiotepa showed that such drugs could eradicate residual bladder tumors and potentially decrease
the use of inlocal r e c ~ r r e n c e .68~ ~Today, , travesical chemotherapy for superficial bladder cancer has become more generally accepted. The main goals of intravesical therapy are to prevent tumor recurrence or tumor progression after TUR of the primary tumor and to treat possible residual tumors after endoscopic surgery. The identification of patients with superficial bladder tumors who are at risk for tumor recurrence and tumor progression after surgical treatment is very important in the selection of candidates for adjuvant or prophylatic use of intravesical the rap^.^, 51 Risk factors include tumor size and grade, multifocality, positive postoperative urine cytology, prostatic urethral involvement, the presence of CIS, and tumors that invade the lamina p r ~ p r i a . ~ Several antitumor agents with definitive activity against CIS or residual tumors after TUR have been developed.29The most commonly studied are thiotepa, doxorubicin (Adriamycin), mitomycin C , epirubicin, ethoglucid, and the nonchemotherapeutic drug bacille Calmette-Gu6rin (BCG). The
From the Department of Surgery, Division of Urology, Children’s Hospital (JLFD) and Brigham and Women’s Hospital, Harvard Medical School (JLFD, KRL), Boston, Massachusetts
UROLOGIC CLINICS OF NORTH AMERICA VOLUME 27 * NUMBER 1 * FEBRUARY 2000
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DUQUE & LOUGHLIN
ideal drug for intravesical therapy would be inexpensive and would have minimal systemic absorption and local toxicity while effectively preventing tumor recurrence and progression after TUR of the primary In the past decade, BCG has emerged as an important intravesical agent because of its economy and effectiveness in prophylaxis against tumor recurrence after TUR of the primary tumor, in the treatment of residual tumors, and in patients with CIS.4l Nevertheless, the toxicity and side effects of intravesical BCG therapy cannot be ignored. Dysuria and urinary frequency occur in about 90% of patients. Furthermore, approximately 24% of patients have fever, and 18% and 8% of patients have malaise and nausea, respectively?' Antituberculosis therapy is required in as many as 6% of the patients treated with BCG owing to the severity of side Some patients may not respond to intravesical BCG therapy. Alternative intravesical therapy with other drugs may be effective in these patients%and in patients with considerable side effects,although other drugs also have limitations and considerable side effects as well. This article focuses on the treatment of superficial bladder cancer with chemotherapic agents. Topics discussed include the effectiveness, side effects, advantages, and disadvantages of each drug. PRINCIPLES AND INDICATIONS
The goal of intravesical therapy varies based on the circumstances in which the drug is used. Prophylactic use after complete resection of a primary tumor in patients with identifiable risk factors for tumor recurrence is usually the most common indication for intravesical chemotherapy; 50% to 70% of patients have tumor recurrence if treated with TUR alone? Intravesical chemotherapy can reduce the incidence of tumor recurrence on a short-term basis, although long-term results have been di~appointing.3~ No evidence suggests that intravesical chemotherapy reduces the incidence of tumor progression on a longterm Other less common indications for intravesical chemotherapy include its therapeutic use for eradicating post-TUR re-
sidual tumors and as an alternative treatment when BCG is not effective or when the side effects of BCG are intolerable. Some basic principles should be followed when administering intravesical chemotherapy. Distilled water is the preferred solution for drug dilution because some studies suggest that it provides better results than saline solutions.56 To achieve satisfactory results, the drug should come in contact with the target urothelium. With the exception of Adriamycin, the drug must be absorbed by the cell to exert its cytotoxic effect Local chemotherapy probably works only against dividing cells, and repeated administrations are required to obtain a response.34A recent study involving mitomycin C and doxorubicin suggested that intensive short-term instillation plus long-term maintenance may offer advantages over less intensive regimens.59The median follow-up in that study was almost 5 years. The dose and concentration of the drug to be administered are important factors in treatment effi~acy.~ The bladder should be emptied immediately before drug instillation, and the patient should be advised to avoid excessive fluid intake to prevent dilution of the agent. The ideal bladder dwell time for chemotherapeutic agents has been controversial, and this period has been chosen empirically by most urologists. Theoretically, the longer the exposure time, the more the drug will exert cytotoxic effects; however, urine production will decrease drug concentration. pH variation may increase the degradation of some chemotherapeutic drugs, decreasing efficacy. Furthermore, a higher drug concentration facilitates diffusion through the urothelium. Another factor to be considered is the length of the interval after TUR before patients should receive intravesical chemotherapy. Several studies have examined the effect of the time interval between TUR and the start of intravesical chemotherapy. Boffiox and co-workers7 reported that patients who began treatment early (less than 2 weeks after TUR) had a longer time to recurrence when compared with patients who began intravesical therapy 2 weeks or longer after resection of the primary tumor. Another study com-
AN OVERVIEW OF THE TREATMENT OF SUPERFICIAL BLADDER CANCER
pared recurrence rates with early instillation (day of TUR) versus delayed instillation (7 to 15 days after TUR) and with short-term (6 months) versus long-term treatment (12 month^).^ Patients who had delayed instillation and short-term treatment had higher recurrence rates when compared with patients who received either early instillation or extended treatment. Early instillation plus prolonged treatment did not improve results in comparison with either protocol alone. All chemotherapic agents have inherent complications. Although higher efficacy theoretically is obtained with higher doses, higher doses are also associated with higher systemic absorption and local side effects. Urethral trauma secondary to catheterization is uncommon, but if trauma is considerable, treatment should be postponed. Because urethral catheterization in the presence of infected urine may cause systemic complications, a urinalysis should be performed before instillati~n.~~ THI OTEPA
Triethylenethiophosphoramide or thiotepa was the first intravesical chemotherapeutic agent used with relative success for treatment of superficial bladder cancer. It is an alkylating agent with a molecular weight of 189 kd that exerts its cytotoxic effect by causing cross-linkage of DNA, RNA, protein, and nucleic acids with subsequent inhibition of nucleic acid synthesis. Thiotepa is not cell cyclespecific. This agent is given intravesically in a variety of schedules to treat superficial bladder cancer or on a prophylactic basis after TUR. Doses range from 30 to 60 mg of thiotepa diluted in 30 to 60 mL of water in a concentration ranging from 0.5 to 1.0 mg/mL for each instillation. Patients are instructed to retain the drug in the bladder for 1 to 2 hours. Instillation is given weekly (total of 4 to 8 weeks), and maintenance doses are given on a monthly basis, usually for up to 1 year. Although some studies have shown that thiotepa can be effective when used as a definitive and prophylactic therapy in superficial bladder cancer, the long-term results pub-
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lished by the Medical Research Working Party on Urological Cancer (Subgroup on Superficial Bladder Cancer) are not encouragi n g 3 Thiotepa did not improve recurrence rates after TUR in comparison with TUR alone; however, the dose for each instillation used in this study was 30 mg diluted in 50 mL of saline solution (0.6 mg/mL), and maintenance doses were given at 3-month intervals. The poor results of this study could be explained by the relatively low dose of thiotepa or the maintenance schedule adopted. The concentration of the drug seems to be more important in terms of intravesical chemotherapy response than the total dose of the drug given."'' Recent data show that 60 mg of the drug diluted in 30 mL of water (2 mg/ mL) can be administered without significant systemic toxicity? A meta-analysis of nine controlled randomized trials using thiotepa with different schedules as prophylactic treatment after TUR revealed a slight decrease in tumor recurrence after drug instillation when compared with TUR alone (Table 1). Five of nine studies showed some benefit (up to 41%), whereas four studies showed no benefit in subjects receiving intravesical thiotepa when compared with controls. The most significant complication of intravesical thiotepa is myelosuppression, which occurs in as many as 20% of the patients.62Leukopenia occurs in 9% to 54% of the patients and thrombocytopenia in 3% to 31%." Systemic absorption occurs owing to the small molecular weight of thiotepa. In general, approximately one third of the drug is absorbed through the urothelium.25Lunglmayr and found that, at a concentration of 1 mg/mL, 19%of the instilled thiotepa was absorbed by the urothelium. Irritative voiding symptoms occur in 12% to 69% of patients. Deaths as a result of treatment are rare, but a few cases have been reportedSz1 ADRlAMYClN Adriamycin (doxorubicin), an anthracycline antibiotic, acts as an antineoplastic drug by binding to DNA base pairs, interrupting DNA replication and transcription, and inhib-
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Table 1. RESULTS OF THIOTEPA PROPHYLACTIC ADMINISTRATION IN 9 CONTROLLED CLINICAL TRIALS IN TERMS OF TUMOR RECURRENCE
Study
Recurrence in Controls (TUR alone) (%)
Recurrence in TUR Thiotepa Group ("YO)
Difference
97 60 64 41 69 66
58 47 65 40 59 39 30 64 40
39* 13* -1 1 10 27* 41, 12* -3
Burnand et all0 Byar and Blackar" Nocks et a14s Asahi et al' Schulman et a1% Koontz et a127 Zincke et a172 Prout et al"' Medical Research Council4"
71
76 37
+
("w
"Differences considered statistically significant (P50.05). Data /rotti Riggs DR, Traynelis CL, et al: Apparent failure of current intravesical chemotherapy prophylaxis to influence the long-term cause of superficial transitional cell carcinoma of the bladder. J Urol 153:1444, 1995; with permission.
iting protein synthesis. Its most toxic effect is seen in the S phase of the cell cycle, although the drug is classified as non-cell cycle phasespecific. Doxorubicin has been indicated mainly in the prophylactic treatment of patients after TUR. Administered doses range from 30 to 100 mg5usually in a concentration of 1 mg/mL (0.5 to 2.0 mg/mL). Schedules are variable, usually ranging from weekly to every 3-week administration. Bladder dwell time is usually 1 to 2 hours. Maintenance schedules are variable; monthly administrations for up to 2 years have been de~cribed.'~ Although a maintenance scheme is widely accepted by most urologists, FlammI5 found that long-term maintenance was not better than short-term treatment (6 weeks with one instillation per week). Neoadjuvant intravesical chemotherapy offers no benefit in terms of tumor r e c ~ r r e n c e . ~ ~ The efficacy of Adriamycin for prophylaxis after TUR of a primary tumor has been reported in controlled series as shown in Table
2. Four of six studies demonstrated a significant advantage of Adriamycin administration in terms of tumor recurrence. Although it is clear that doxorubicin can decrease tumor recurrence, series with long-term follow-up have failed to show any improvement in regard to tumor progression in either stage or survival.31Recently a group from Japan has suggested that the intravesical instillation of Adriamycin plus verapamil can offer advantages in terms of tumor recurrence after TUR in comparison with Adriamycin alone with a median follow-up of 38.5 months.42Longer follow-up is needed to confirm this result. Systemic side effects and toxicity of Adriamycin are uncommon owing to its high molecular weight (580 kd), causing only minimal absorption of the drug into the circulation. Systemic reactions are seen in 1.2% to 5.1% of the patients64;however, local side effects are relatively common. Chemical cystitis as defined by dysuria and urinary frequency is the most common side effect and may occur in
Table 2. TUMOR RECURRENCE IN PATIENTS TREATED WITH ADJUVANT DOXORUBICIN (POST-TUR) IN CONTROLLED SERIES Recurrence in Controls (TUR alone) Study
("/.I
Niijima et aP4 Zincke et a172 Rubben et alSs Akaza et al' Kurth et a P Ali-el-Dein et a12
62 71 61 33 71 37
'Differences considered significant.
Recurrence in TUR + Doxorubicin Group (%) 45 32 56 25 52 66
Difference
("4 17* 39* 5 8 19, 29'
AN OVERVIEW OF THE TREATMENT OF SUPERFICIAL BLADDER CANCER
4% to 56% of patients.&Hematuria occurs in 14% to 41% of patients. Other less common reactions with intravesical Adriamycin include fever, gastrointestinal effects, and, rarely, allergic reactions. Reduced bladder capacity was reported in 16% of patients in one s t ~ d y . Usually, ~" symptoms related to intravesical Adriamycin are relieved with treatment interruption, and sequelae are rarely seen.
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rence and length of disease-free interval. With a median follow-up of 7 years, the same group reported a slight advantage of five instillations over a single instillation, but no definitive conclusions could be drawn. One and five instillations resulted in decreased recurrence rates in comparison with controls; however, no benefit was seen regarding progression rates with either therapy.& Another group has suggested that 40 mg of mitomycin given for 6 months is superior to 30 mg for 12 months.67Solsona and coMlTOMYClN C w o r k e r ~reported ~~ that a single instillation of 30 mg of mitomycin after TUR in patients with low-risk superficial bladder cancer ofMitomycin C is an alkylating agent with a fered advantages when compared with no molecular weight of 334 kd. Its mechanism of treatment only on a short-term basis. Solsona action has not been totally clarified, although and colleagues suggested that cell implantasome evidence suggests that it acts by bindtion as a mechanism of early tumor recuring to DNA, resulting in synthesis inhibition rence could be controlled with a single dose and strand breakage. Mitomycin C is most of mitomycin after TUR in patients with lowsensitive in the late G, and early S phase, but overall it is considered cell cycle-non~pecific.~ risk superficial bladder cancer. This assumption was based on the fact that patients who Instillation schedules are variable. Doses received mitomycin after TUR had signifirange from 20 to 60 mg diluted in water in a cantly more late than early recurrences, and concentration ranging from 0.5 to 2.0 mg/mL, there was no relationship between early and with bladder dwell time ranging from 1 to 2 late recurrences among the controls (TUR hours. Response rates seem to increase with only). The efficacy of the prophylactic use of increasing doses?' The drug is usually adminmitomycin in other controlled trials is shown istered weekly for a period of 8 weeks, folin Table 3. lowed by monthly maintenance doses for up Because of its high molecular weight, abto 1 year.22Although the role of maintenance sorption of mitomycin in the systemic circulatherapy is controversial, in a randomized protion is low, and, systemic reactions are not spective controlled trial, Tolley and co-workcommon. Allergic reactions occur in 3% to e r analyzed ~ ~ ~the prophylactic role of a single dose of mitomycin after TUR (40 mg) com19% of patients. Contact dermatitis is seen in pared with five instillations over a 1-year peas many as 12%, and leukopenia and thromriod. They concluded that repeated instillabocytopenia are uncommon.64Reduced bladtions of 40 mg of intravesical mitomycin der capacity is not frequent but has been offered advantages in terms of tumor recurnoted by some researchers. The most comTable 3. EFFICACY OF PROPHYLACTIC MlTOMYClN IN CONTROLLED SERIES Recurrence in Controls (TUR only) Study Huland and Otto" Niijima et a P Kim and Lee" Rubben et als4 Akaza et all Krege et aI2" Tolley et alM 'Differences considered significant.
("/.I 50 62 82 42 33 46 54
Recurrence in Mitomycin TUR Group (%)
+
7 57 81
35 24 27 32
Difference
("A) 43* 5 1 7 9 19* 22'
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DUQUE & LOUGHLIN
mon local side effects are dysuria and urinary frequency, occuring in as many as 41% of patients." EPlRUBlClN
Epirubicin (4'-epidoxorubicin)is an anthracycline derivate of doxorubicin. The mechanism of action is similar to that of doxorubicin (DNA synthesis inhibition with further protein synthesis inhibition), with a more favorable toxicity p r ~ f i l eDoses .~ range from 50 to 80 mg/mL at a concentration of 1.0 to 1.6 mL. Instillation is usually initiated 1 to 2 weeks after TUR and is performed weekly for a total of 8 weeks and then monthly to complete 1 year of treatment.2Patients are instructed to hold the drug in the bladder for 1 to 2 hours after administration. In an initial study car59% of ried out by Kurth and ~o-workers,~~ patients had a complete response, and, with a mean follow-up of 35 months, 62% of the patients with an initial complete response were alive without recurrences. One third of the patients analyzed had a durable complete response. Prospective controlled series have shown that epirubicin can significantly decrease tumor recurrence even when instilled in a single-dose manner after TUR.48Although an initial study performed in Japan suggested that epirubicin had efficacy similar to that of Adriamycin>l a more recent study comparing the efficacy of epirubicin and doxorubicin has shown that epirubicin is, in fact, more effective than doxorubicin in terms of tumor recurrence after TUR. Epirubicin was also associated with lower toxicity.* In this controlled randomized study, two doses of epirubicin were used-50 and 80 mg. Although there were no significant differences in terms of simple recurrence rates, the recurrent rates per 100 patient-months (defined as the total number of positive cystoscopic studies irrespective of the number of tumors divided by the total months of follow-up from the date of the last TUR at study entry until the final cystoscopic examination multiplied by 100) were statistically different between the two groups. Side effects were higher in the doxorubicin group than in the 50- and 80mg epirubicin groups. Systemic toxicity of
epirubicin was not observed, although an allergic reaction rate of l % has been repeated in other ~eries.4~ The most common side effects are mild urinary symptoms. A contracted bladder occurs in less than 1%of patients? ETHOGLUCID
Ethoglucid (triethylene glycol diglycidyl ether) is a podophyllin derivative with a molecular weight of 262 kd. Its mechanism of action is similar to that of an alkylating agent.5 The dose used is usually about 1 g of the drug diluted in 100 mL of sterile water (lYo ~ o l u t i o n ) . ~Initial ' instillation is performed 1 to 2 weeks after TUR, followed by four to ten instillations performed on a weekly basis. Maintenance doses are given monthly for up to 1 year. Bladder dwell time is 1 hour. Recent data from a controlled randomized trial with a long follow-up suggest that patients undergoing prophylactic intravesical ethoglucid therapy have a prolonged time to first recurrence and a decrease in recurrence rates in comparison with patients treated with TUR alone. Ethoglucid did not influence tumor progression to muscle invasive disease and survival in comparison with TUR alone.3I Because of its high molecular weight, ethoglucid is poorly absorbed, and systemic side effects are rare. A recent series reported fever and allergic skin reaction in approximately 4% of patient^.^^ No myelosupression was seen in that study; however, a few cases have been reported in other series. Local side effects such as urgency and frequency are reported in 3% to 59%of studies." OTHER AGENTS
Mitoxantrone is a synthetic, intercalating, anthraquinone-based agent related structurally and in its mode of action to doxorubicin.43In a prospective randomized controlled trial, patients who received mitoxantrone did not have improved tumor recurrence rates in comparison with patients who underwent TUR only,I6 although the time to recurrence
AN OVERVIEW OF THE TREATMENT OF SUPERFICIAL BLADDER CANCER
was longer in patients who received intravesical chemotherapy. No advantage in terms of tumor progression was noted. Chemical cystitis occurred in 11%of patients. Severe reactions are rare.64 N-trifluoroacetyladriamycin-14-valerate (AD 32) is an anthracycline that has proved to be less toxic and therapeutically superior to doxorubicin in animal models. Recent data suggest that it may be beneficial in the treatment of superficial bladder cancer, but no prospective randomized controlled trial has proved its efficacy in decreasing tumor recurrence and progression after treatment of a primary 1esi0n.I~ COMBINED INTRAVESICAL CHEMOTHERAPY
Because no drug available for intravesical chemotherapy is 100%effective in eradicating bladder tumors or in preventing tumor recurrence and because tumor progression seems to occur regardless of whether patients receive prophylactic local chemotherapy, a combination of two or more drugs has been investigated. The results of three studies combining mitomycin and Adriamycin have been published in the last 7 years. Isaka and co-workersZ4treated 40 patients with superficial bladder cancer with a combination of 20 mg of mitomycin on day 1 and 30 mg of doxorubicin on day 2 each week for 5 consecutive weeks (20 patients received prophylaxis after TUR and 20 were treated for multiple recurrences). A complete response was seen in 45% of the patients treated for multiple recurrences. Of patients receiving prophylactic instillation after TUR of primary multiple or high-grade tumors, 66%were free of recurrence with a mean follow-up of 14 months. Fukui and co-worker~'~ treated 101 patients with superficial bladder cancer using a similar schedule, the same dose of mitomycin, and 40 mg of doxorubicin. Fifty-one patients had a complete response (23 patients with stage Tis and 28 with stage Ta or T1 disease). These patients were randomized into two arms: (1) nonmaintenance and (2) monthly maintenance for 1 year. Patients with stage
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Tis tumors did significantly better with a maintenance schedule in terms of tumor recurrence rates, whereas maintenance therapy did not improve recurrence rates significantly in patients with papillary tumors. Mean follow-up ranged from 7 to 44 months. Half of the patients had significant local side effects (voiding symptoms). Sekine and co-workers60treated 43 patients with CIS with a combination of 20 mg of mitomycin on day 1 and 40 mg of doxorubicin on day 2 once a week for 5 weeks. A complete response was achieved in 74% of the patients after initial therapy. Among the responders, 41% had a local recurrence. Maintenance therapy with either mitomycin plus doxorubicin or mitomycin alone did not improve recurrence rates when compared with no maintenance therapy. The median followup was almost 5 years. COMBINED INTRAVESICAL CHEMOTHERAPYAND IMMUNOTHERAPY
Combined chemotherapy and immunotherapy may have a synergistic antitumor effect because their mechanisms of action are different. Potential benefits in terms of tumor recurrence and progression could be achieved with combined therapy. A group from Finland53studied the combination of intravesical BCG and mitomycin for CIS. Patients were randomized in two arms. One group received only mitomycin (20 to 40 mg), and the second group received a combination of mitomycin and BCG (75 mg). Combined therapy was associated with better results when compared with mitomycin alone in terms of complete response, disease-free interval, and tumor recurrence. Mean follow-up was 33 months. The same group from Finland52performed a subsequent study analyzing 188 patients with rapidly recurring stage Ta or T1 tumor. These patients were randomly treated with the same doses of mitomycin or mitomycin plus BCG. N o difference was observed between the groups in terms of tumor recurrence and disease-free interval with a mean follow-up of 34 months. Witjes and c o - w ~ r k e r shave ~ ~ reported the
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results of a randomized phase 111 protocol comparing ten administrations of mitomycin with four administrations of mitomycin plus six of BCG, all performed on a weekly basis following TUR in patients with moderate and high-risk superficial bladder cancer. Patients with CIS were included in this study. No significant differences were found between the two groups in terms of tumor recurrence, tumor progression, or systemic toxicity. COMPARATIVE SERIES
No clear evidence suggests that any drug is superior to another in terms of tumor recurrence, progression, and survival.33One recent prospective randomized study2 suggested that epirubicin was superior to doxorubicin in terms of recurrence and toxicity. A group from Portugal reported equal efficacy when comparing chemoprophylactic use of mitomycin with epirubicin in a noncontrolled randomized trial.I2Several comparisons between chemotherapy (mitomycin) and immunotherapy (BCG) have been made in recent years, and the results are contr~versial.~~ A randomized clinical trial conducted by Krege and coworkersZ6showed that the risk of recurrence was the same with BCG versus mitomycin therapy. In a randomized trial comparing the prophylactic use of mitomycin, Tice BCG, and RIVM-BCG, Vegt and c o - w ~ r k e r sshowed ~~ that mitomycin and RIVM-BCG were equally effective in terms of tumor recurrence, and that mitomycin was more effective than Tice BCG. Lundholm and c o - ~ o r k e r sfound ~ ~ that BCG was superior for recurrence prophylaxis (patients in the BCG group had fewer recurrences and a significantly longer time to treatment failure when compared with patients treated with mitomycin). Witjes and co-workem7’randomized 342 patients to receive BCG or mitomycin after TUR. With a median follow-up of 7 years, they concluded that the efficacy of both treatments was the same in regard to tumor recurrence; however, mitomycin was more effective than BCG in terms of tumor progression in patients without CIS. Malmstrom and c o - ~ o r k e r shave ~ ~ reported their updated data (from the Lundholm study3s) comparing mitomycin with BCG
with a median follow-up of 64 months. BCG was superior to mitomycin for recurrence prophylaxis, but no difference was found regarding tumor progression and survival. INTRAVESICAL CHEMOTHERAPY IN THE TWENTY-FIRST CENTURY
Research efforts have focused on defining the mechanism of action of the chemotherapic agents and factors influencing drug activity in an attempt to increase the efficacy of these agents. In vitro studies suggest that interferon-a may increase the efficacy of doxorubicin and mitomycin by decreasing cell proliferation in human bladder carcinoma cell lines.j6 Recently obtained data support the assumption that there is a linear correlation between drug uptake in the bladder tissues and drug concentration in the urine.ls Future prospective studies using higher drug concentration instead of higher total dose may increase the efficacy of intravesical chemotherapy. Pharmacokinetic studies have shown that electromotive delivery of mitomycin enhances the penetration of the drug into viable bladder wall Preliminary clinical data comparing electromotive administration of mitomycin with standard administration of the drug show similar complete response rates in the two groups but suggest that, among responders, electromotive administration may offer some advantage in terms of tumor recurrence on a short-term b a s k 9 Absorption enhancers such as dimethyl sulfoxide may provide rationale for future clinical trials involving intravesical chemotherapy for superficial bladder cancers. Tumor histology is correlated with tumor sensitivity to mitomycin. Well-differentiated bladder tumors have a greater sensitivity to mitomycin than undifferentiated invasive tum o r ~ These . ~ ~ data confirm the importance of patient selection in the success of drug treatment. Recent experimental data suggest that photodynamic therapy with 5-aminolevulinic acid can enhance the effect of mitomycin on a bladder cancer cell line, suggesting a possible role in combined therapy.I3 Intravesical chemotherapy can provide a decrease in tumor recurrence rates on a short-
AN OVERVIEW OF THE TREATMENT OF SUPERFICIAL BLADDER CANCER
and long-term basis.49A prolonged diseasefree interval is achieved with adjuvant intravesical chemotherapy. BCG seems to be the best available prophylactic treatment for superficial bladder cancer, although chemotherapy may provide similar results in selected patients. Studies with long-term follow-up show that tumor progression and survival are not affected by post-TUR intravesical chemotherapy. Further studies focusing on risk factors and tumor biology will be helpful in the selection of ideal patients for intravesical Chemotherapy. References I . Akaza H, Isaka 5, Koiso K, et al: Comparative analysis of short-term and long-term prophylactic intravesical chemotherapy of superficial bladder cancer: Prospective, randomized, controlled studies of the Japanese Urological Cancer Research Group. Cancer Chemother Pharmacol2O(suppl):91, 1987 2. Ali-cl-Dein B, el-Baz M, Aly AN, et al: Intravesical epirubicin versus doxorubicin for superficial bladder tumors (stages pTa and pT1): A randomized prospective study. J Urol 158:68, 1997 3. Anonymous: The effect of intravesical thiotepa on tumor recurrence after endoscopic treatment of newly diagnosed superficial bladder cancer: A further report with long-term follow-up of a Medical Research Council Working Party on Urological Cancer, Subgroup on Superficial Bladder Cancer. Br J Urol 73:632, 1994 4. Asahi T, Matsumura Y, Tanahashi T, et al: The effects of intravesical instillation of thio-tepa on the recurrence rate of bladder tumors. Acta Med Okayama 34:43, 1980 5. Badalament RA, Farah RN: Treatment of superficial bladder cancer with intravesical chemotherapy. Semin Surg Oncol 13335, 1997 6 . Batts CN: Adjuvant intravesical therapy for superficial bladder cancer. Ann Pharmacother 261270, 1992 7. Bouffioux CH, Denis L, Oosterlinck W, et al: Adjuvant chemotherapy of recurrent superficial transitional cell carcinoma: Results of a European Organization for Research on Treatment of Cancer, randomized trial comparing intravesical instillation of thiotepa, doxorubicin and cisplatin. J Urol I48:297, 1992 8. Bouffioux CH, Kurth KH, Bono A, et al, and the members of the European Organization for Research and Treatment of Cancer Genitourinary Group: Intravesical adjuvant chemotherapy for superficial transitional cell bladder carcinoma: Results of 2 European Organization for Research and Treatment of Cancer randomized trials with mitomycin C and doxorubicin comparing early versus delayed instillations and short-term versus -long-term treatment. J Urol 153934, 1995 9. Brausi M, Campo B, Pizzocaro G, et al: Intravesical electromotive administration of drugs for treatment of superficial bladder cancer: A comparative phase I1 study. Urology 51:506, 1998
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10. Bumand KG, Boyd PJR, Mayo ME, et a]: Single dose intravesical thiotepa as a n adjuvant to cystodiathermy in the treatment of transitional cell bladder carcinoma. Br J Urol 48:55, 1976 11. Byar D, Blackard C: Comparisons of placebo, pyridoxine, and topical thiotepa in preventing recurrence of stage I bladder cancer. Urology 10556, 1977 12. Da Silva FC, Ferrito F, Brandao T, et al: 4’-Epidoxombicin versus mitomycin C intravesical chemoprophylaxis of superficial bladder cancer. Eur Urol 21:42, 1992 13. Datta SN, Allman R, Loh C, et al: Effect of photodynamic therapy in combination with mitomycin C on a mitomycin-resistant bladder cancer cell line. Br J Cancer 76312, 1997 14. Di Stasi SM, Vespasiani G, Giannantoni A, et aI: Electromotive delivery of mitomycin C into human bladder wall. Cancer Res 57875, 1997 15. Flamm J: Long-term versus short-term doxorubicin hydrochloride instillation after transurethral resection of superficial bladder cancer. Eur Urol 17119, 1990 16. Flamm 1, Donner G, Oberleitner S, et al: Adjuvant intravesical mitoxantrone after transurethral resection of primary superficial transitional cell carcinoma of the bladder: A prospective randomized study. Eur J Cancer 31A143, 1995 7. Fukui I, Kihara K, Sekine H, et al: Intravesical combination chemotherapy with mitomycin C and doxorubicin for superficial bladder cancer: A randomized trial of maintenance versus no maintenance following a complete response. Cancer Chemother Pharmacol 3O(suppl):37, 1992 8. Gao X, Au JL, Badalament RA, et al: Bladder tissue uptake of mitomycin C during intravesical therapy is linear with drug concentration in urine. Clin Cancer Res 4:139, 1998 19. Greenberg RE, Bahnson RR, Wood D, et al: Initial report on intravesical administration of N-trifluoroacetyladriamycin-14-valerate(AD32) to patients with refractory superficial transitional cell carcinoma of the urinary bladder. Urology 49:471, 1997 20. Herring HT: The treatment of vesical papilloma by injections. BMJ 23398, 1903 21. Hollister D Jr, Coleman M Hematologic effects of intravesicular thiotepa therapy for bladder carcinoma. JAMA 244:2065, 1980 22. Huben RP: Intravesical chemotherapy versus immunotherapy for superficial bladder cancer. Semin Urol Oncol 14:17, 1996 23. Huland H, Otto U Mitomycin instillation to prevent recurrence of superficial bladder carcinoma: Results of a controlled prospective study in 58 patients. Eur Urol 9:84, 1983 24. Isaka S, Okano T, Abe K, et al: Sequential instillation therapy with mitomycin C and adriamycin for superficial bladder cancer. Cancer Chemother Pharmacol 3O(suppl):41, 1992 25. Jones HC, Swinney J: Thiotepa in the treatment of tumors of the bladder. Lancet 2615, 1961 26. Kim HH, Lee C Intravesical mitomycin C instillation as a prophylactic treatment of superficial bladder tumor. J Urol 141:1337, 1989 27. Koontz WW Jr, Prout GR Jr, Smith W, et al: The use of intravesical thio-tepa in the management of noninvasive carcinoma of the bladder. J Urol 125:307, 1981 28. Krege S, Giani G, Meyer R, et al: A randomized multicenter trial of adjuvant therapy in superficial
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Kevin R. Loughlin, MD Brigham and Women’s Hospital 45 Francis Street Boston, MA 02115