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Epirubicin

A Review of its Intravesical Use in Superficial Bladder Cancer

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Abstract

Summary

The anthracycline epirubicin has been investigated for intravesical use in patients with superficial bladder cancer. In multicentre, randomised trials, prophylaxis with intravesical epirubicin 30 to 80mg after transurethral resection (TUR) was more effective than no prophylaxis in the prevention of disease recurrence. Intravesical prophylaxis with epirubicin was as effective as that with equivalent dosages of doxorubicin after TUR. Data are conflicting concerning the relative efficacy of intravesical epirubicin and bacillus Calmette-Guerin (BCG) in patients at intermediate risk of recurrence after TUR, but epirubicin was less effective than BCG in those at high risk. The efficacy and tolerability of prophylaxis with epirubicin relative to that with mitomycin is not yet established. The efficacy of epirubicin as prophylaxis after TUR in combination with BCG or interferon-α-2b, or as treatment in patients with superficial bladder cancer has been evaluated in small, noncomparative trials, but requires clarification.

Adverse events associated with intravesical epirubicin were generally mild and transient. The most common adverse events were localised to the bladder (cystitis, haematuria and urinary tract infection). Systemic adverse events (cardiac, haematological or related to hypersensitivity) were not reported in mn, and when reported generally occurred ited generally occurred in ≤5% of patients who received the drug. Intravesical epirubicin was generally tolerated as well as intravesical doxorubicin and was associated with a lower incidence of mild chemical cystitis in 1 clinical trial. The incidence of adverse events associated with intravesical epirubicin was markedly lower than that associated with intravesical BCG.

Conclusions: Intravesical epirubicin has shown efficacy in preventing disease recurrence after TUR of superficial bladder cancer. In comparison with equivalent dosages of doxorubicin, the efficacy of epirubicin for this indication is generally similar, and the tolerability profile may be more favourable. Epirubicin is less effective than BCG as intravesical prophylaxis in patients at high risk of recurrence after TUR; the relative efficacy of epirubicin and BCG after TUR in patients at intermediate risk is not yet clear. Intravesical epirubicin is generally tolerated better than BCG. Intravesical epirubicin may be used as prophylaxis after TUR in patients who are at low or intermediate risk of recurrence of superficial bladder cancer.

Pharmacodynamic Properties

Epirubicin, an epimer of the anthracycline doxorubicin, is an antineoplastic agent that inhibits DNA replication, transcription and repair by binding to the nucleic acid. Epirubicin was at least as cytotoxic as doxorubicin in vitro in bladder tumour cell lines. It was less cytotoxic to normal than to neoplastic transitional epithelial cells. Importantly, epirubicin is less cytotoxic than doxorubicin to haematopoietic progenitor cells in vitro and to cardiac tissue in vivo.

Resistance to epirubicin was reversed in bladder tumour cell lines in vitro by verapamil, valspodar, increasing pH, estramustine, lonidamine or meglumine-γ-linoleic acid. In patients with superficial bladder cancer, combination therapy with epirubicin and verapamil achieved higher concentrations of the drug than epirubicin alone in neoplastic and normal transitional epithelium prior to TUR, and this was correlated with clinical response.

Pharmacokinetic Properties

Before it can be absorbed systemically, intravesically administered epirubicin must enter the transitional epithelial cells which line the bladder. 58 to 84% of each dose was recovered from the bladder in washes and voided urine after each intravesical instillation of epirubicin 30 to 80mg. Tumours absorbed 2- to 10-fold more epirubicin than normal transitional epithelium in patients with superficial bladder cancer who received the drug intravesically. Systemic absorption of intravesically administered epirubicin is minimal. Peak plasma concentrations were 3 to 9 μg/L in most patients who received intravesical epirubicin 20 to 50mg.

Epirubicin metabolism is similar to that of doxorubicin except that, unlike its stereoisomer, epirubicin undergoes β-glucuronidation. After intravenous administration, the terminal elimination half-life of epirubicin (15 to 45 hours) is 40 to 70% shorter than that of doxorubicin, probably because of the difference in β-glucuronidation. Clearance of intravenously administered epirubicin was 40 to 87 L/h. The primary route of excretion was the bile, and patients with hepatic dysfunction exhibited elevated plasma drug concentrations and reduced clearance compared with those with normal hepatic function when they received epirubicin intravenously.

Clinical Efficacy in Superficial Bladder Cancer

Prophylaxis. Intravesical epirubicin was effective in the prevention of tumour recurrence after TUR in multicentre, randomised clinical trials in patients with superficial bladder cancer. The optimal dosage regimen has not yet been established. However, single dose epirubicin was as effective as an induction and maintenance protocol in patients at low risk of recurrence, but was less effective in patients at intermediate or high risk of recurrence. Overall recurrence rates were lower with epirubicin 40 to 80mg (single dose or induction and maintenance; 0.072 to 0.186 per year) than with no prophylaxis (0.241 to 0.378 per year). Similarly, mean recurrence-free intervals were longer with epirubicin than with no prophylaxis.

The overall efficacy of intravesical prophylaxis with epirubicin after TUR was similar to that with identical dosages of doxorubicin (induction and maintenance). Overall recurrence rates were 0.100 or 0.110 per year with epirubicin 50mg, 0.072 per year with epirubicin 80mg and 0.180 or 0.142 per year with doxorubicin 50mg in 2 trials; the difference was statistically significant when epirubicin (both doses combined) was compared with doxorubicin in 1 of these trials. However, in 2 other studies, simple recurrence rates were similar with epirubicin 30mg (25% in both studies) or doxorubicin 30mg (27 or 28%). Mean recurrence-free intervals were similar in patients who received epirubicin 30 to 80mg or doxorubicin 30 or 50mg.

The overall clinical efficacy of induction and maintenance prophylaxis with epirubicin versus that with bacillus Calmette-Guerin (BCG) varied in clinical trials. Overall recurrence rates did not differ significantly with epirubicin 50mg (0.186 to 0.252 per year) or BCG 150mg or 5 × 108 colony forming units [cfu] (0.134 to 0.167 per year); similarly, recurrence rates did not differ significantly between these 2 agents in patients with Ta, G1, G2, single, multiple, primary or recurrent tumours. However, recurrence rates were consistently significantly higher with epirubicin than with BCG in patients with T1 and/or G3 tumours. The trends in recurrence-free intervals were similar to those in recurrence rates in trials of prophylactic epirubicin versus BCG. In 1 large trial in patients at intermediate or high risk of recurrence after TUR, overall recurrence-free rates 2 years after TUR were significantly lower with epirubicin than with BCG; this trial was reported as an abstract. In contrast, recurrence-free rates were similar with the 2 agents 2, 3 or 5 years after TUR in smaller trials in patients at low, intermediate or high risk of recurrence. Data are insufficient to establish the efficacy of epirubicin in comparison with interferon-α-2b or mitomycin.

Similar to other intravesical agents, epirubicin did not appear to reduce the rate of progression of tumours which recurred after TUR. The rate of progression of tumours to stage T2 (muscle-invasive disease) was generally similar with epirubicin and doxorubicin or BCG.

Prophylaxis with epirubicin in combination with BCG was evaluated in a few clinical trials. In 1 comparative trial, recurrence-free interval tended to be longer with epirubicin and BCG than with BCG alone after TUR; recurrence and progression rates appeared to be lower with the combination of epirubicin and BCG but did not differ significantly between the 2 regimens. In addition, combination prophylaxis with epirubicin and interferon-α-2b after TUR tended to be more effective than epirubicin alone, interferon-α-2b or no prophylaxis in trials in patients with superficial bladder cancer.

Treatment. Intravesical epirubicin 30 to 60mg as treatment achieved variable complete response rates (range 6 to 67%) in noncomparative trials. In a small number of patients with carcinoma in situ, treatment with epirubicin 30 to 80mg achieved dose-related complete response rates of 43 to 70%.

Tolerability

The overall incidence of adverse events in trials of intravesical epirubicin 50mg ranged from 16 to 25%. The frequency of adverse events tended to increase with epirubicin dose but not number of instillations. Most adverse events associated with intravesical epirubicin were mild and transient; the most common were localised to the bladder and included chemical cystitis (10 to 38% of patients), urinary tract infection (2 to 13%) and haematuria (2 to 33%). Contracted bladder or haemorrhagic cystitis occurred in 1 to 6% of patients in a few trials.

Systemic adverse events were not reported in many trials, and usually occurred in ≤5% of patients who received intravesical epirubicin. Cardiac adverse events (myocardial infarction, cerebrovascular accident, angina pectoris or atrioventricular block) were reported in only 2 studies, and occurred in 2 to 9% of patients. Thrombocytopenia and haemoglobinaemia each occurred in 3% of patients in 2 different trials, but otherwise there were no reports of myelosuppression. Hypersensitivity was reported in 0 to 8% of patients in different trials; 1 patient died of a severe allergic reaction after receiving intravesical epirubicin. Nonspecific systemic symptoms (flu-like symptoms, malaise, fever, nausea, vomiting, anorexia or rash) were reported in 0 to <5% of patients who received intravesical epirubicin.

Overall, the type and incidence of local adverse events was similar with epirubicin and doxorubicin. The incidence of mild chemical cystitis tended to be lower with epirubicin 50 or 80mg (8 to 19%) than with doxorubicin 50mg (21 or 25%); the difference was significant in 1 trial. Systemic adverse events occurred in no epirubicin recipients and 5% of doxorubicin recipients in 1 study, but were not reported in other comparative trials.

The incidence of local adverse events was usually lower with epirubicin than with BCG in comparative trials. Cystitis occurred in 25 to 38% of recipients of epirubicin 50mg and 67 to 79% of recipients of BCG 150mg or 5 × 108 cfu in 3 trials; the incidence of this adverse event was similar with epirubicin 80mg and BCG 75mg (62 or 61%) in a fourth trial. Haematuria occurred less often in patients who received epirubicin 50mg (13 to 16% of patients) than in those who received BCG 150mg or 5 × 108 cfu (23 or 24% of patients), but more often with epirubicin 80mg than BCG 75mg (26 vs 10% of patients). Adverse events caused temporary delays in treatment more often with epirubicin than with BCG. Nonspecific systemic adverse events occurred markedly less often with epirubicin (0 to 18%) than with BCG (13 to 31%) in comparative trials.

The incidence of cystitis was similar with epirubicin or mitomycin (11%) in a single trial, but the comparative tolerability of these 2 agents has not been fully investigated. In trials of combination prophylaxis with epirubicin and BCG, the incidence of adverse events may have been related to the treatment regimen, and was lower with epirubicin in combination with BCG than with BCG alone in 1 comparative trial. Adverse events were similar in patients who received epirubicin alone or epirubicin in combination with interferon-α-2b as prophylaxis in clinical trials.

Dosage and Administration

Intravesical epirubicin is indicated for prophylaxis after TUR or for treatment in patients with superficial bladder cancer. There is no recommended dosage, but the most common dosage for prophylaxis is induction with epirubicin 50mg in 50ml saline once a week for 4 weeks, then maintenance with the same dose once a month for 11 months, according to the manufacturer. For treatment, the dosage suggested by the manufacturer is epirubicin 50mg once a week for 8 weeks; the dose can be increased to 80mg in patients with carcinoma in situ, depending on individual tolerability.

Each dose of epirubicin should be instilled in the bladder through a small catheter and retained for 1 hour. Patients should avoid fluids for 12 hours before each instillation and not void until the end of the instillation. Patients who have already received the maximum cumulative dose of other anthracyclines, who have a history of hypersensitivity to anthracyclines or who developed marked myelo-suppression during previous anthracycline exposure should not receive intravesical epirubicin.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Susan V. Onrust, Lynda R. Wiseman & Karen L. Goa

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  1. Susan V. Onrust
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  2. Lynda R. Wiseman
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Correspondence to Susan V. Onrust.

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Onrust, S.V., Wiseman, L.R. & Goa, K.L. Epirubicin. Drugs Aging 15, 307–333 (1999). https://doi.org/10.2165/00002512-199915040-00006

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