Intravesical chemotherapeutic agents
Thiotepa (triethylene thiophosphoramide)
Thiotepa was first used for intravesical therapy of superficial bladder cancer by Jones and Swinney. It is an alkalizing agent that acts by cross-linking nuclear acids and proteins. It has generally been administered at a dose of 1 mg/ml in either 30 mg in a 30-ml bolus or 60 mg in a 60-ml bolus, with the drug being retained for 2 h. A variety of regimens, including weekly x 6-8 followed by monthly for a year, were frequently used in the 1970s and the early 1980s. It produces complete response rates in approximately 35% of cases and partial remission rates in a further 25% which is somewhat less than other intravesical chemotherapeutic agents. It has also been utilized as a prophylactic agent, with a marked reduction of recurrence rate of 25% over the next 2 years compared with untreated tumours.
Because of its low molecular rate (198 Da) thiotepa may readily be absorbed through the bladder wall and can cause marrow suppression in 50-20% of patients. Although it is still utilized occasionally as an active agent, because of its potential toxicity its utilization has tended to fall compared with both other intravesical chemotherapeutic agents and immu-notherapeutic agents such as bacille Calmette-Guerin. There is no evidence that thiotepa prevents progression of superficial disease.
Adriamycin (doxorubicin hydrochloride)
Adriamycin was isolated in 1963 by aerobic fermentation of Streptomyces peucetius, a variant of S. caesius as an anti-neoplastic antibiotic agent. Chemically, it is an anthracycline excerpting its cytostatic activity through binding specifically with DNA by intercalation between adjacent-based pairs of the double helix, thus interrupting DNA synthesis and also protein synthesis. The utilization of this agent intravesically showed complete response compared with transurethral resection alone, which ranged between 5% and 39% and its benefits when used in a prophylactic fashion in a reduction of recurrence rate between 20% and 40% compared with transurethral resection alone. From the present available data we can see that for patients with low and intermediate risk superficial bladder tumours the recurrence rate with Adriamycin compared with Bacille Calmette-Guerin is lower, but in high-risk tumours Bacille Calmette-Guerin is superior in reducing the recurrence rate.
Adriamycin has largely been superseded by epirubicin both in its systemic activity in other cancers and in the treatment of superficial bladder disease, but the drug can still be used safely because of its relatively high molecular weight with minimal systemic toxicity.
Epirubicin
Epirubicin differs from doxorubicin by the epimerization of the hydroxyl group at position 4 of the amino acids. It was developed with a view to enhancing the therapeutic activity and has had a significant decrease in side-effects when given parentally as compared with doxorubicin. Its dose, however, not dissimilarly to Adriamycin, has a series of local toxicity profiles and in studies using epirubicin up to 30% of patients are discontinued intravesical treatment because of local toxicity. A significant paper showing the utility of intravesical agents overall was that of Oosterlinck et al., which demonstrated that a single installation of 80 mg of epirubicin in all grades (low, intermediate and high risk superficial bladder cancer) produced a 50% reduction in recurrence. Figures were confirmed by the Medical Research Council (Medical Research Council) in a series of studies utilizing thiotepa and epirubicin and mitomycin C. A single installation of a chemotherapeutic agent (either epirubicin or mitomycin C), given within 24 h of resection of the superficial bladder cancer, has this persistent and forecastable benefit and should be considered standard therapy.
Mitomycin C
Mitomycin C is an antibiotic chemotherapeutic agent that acts by inhibition of DNA synthesis. It has a high molecular weight of 334 Da, such that there is little in the way of systemic absorption from the bladder. In 1975, Mishina et al. reported the results of a 7-year-long phase II trial using intravesical mitomycin C for superficial bladder cancer. Fifty patients received 20 mg of mitomycin C and 20 ml of saline, which they retained for an average of 3 h, but they were asked to retain it for as long as possible. Patients received three installations per week for 7 weeks, and complete response was achieved in 44% of patients and partial responses in a further 16%. This demonstrated that mitomycin C alone could eradicate tumours from the bladder without preliminary resection.
In 1983, Harrison et al. validated this study in 23 patients utilizing the same intensive regime, although the duration of installation was limited to 1 h but with an overall response rate of 77%. It has already been confirmed that a single installation following transurethral resection of prostate (transurethral resection of prostate), mitomycin C has the same benefit as epirubicin. Because of the proven efficacy of mitomycin C, in patients debilitated by general medical problems such as severe cardiac or respiratory disease, which are exacerbated by bleeding from superficial bladder lesions thus rendering the patient unfit for an anaesthetic and surgery, naturalisation of the Mishima regimen with mitomycin C at either the 20 or 40 mg in 40 mis dose can often stop the bleeding and allow time for the patient to become fitter before resection and additional therapy can be given.
SIDE-EFFECTS
Because of its relatively large molecular size specific side-effects are small but do include chemical cystitis with associated pain and haematuria. A specific effect relating only to mitomycin usage is contact dermatitis, which is frequently on the hands and around the genitalia and occasionally on the feet. A systematic review of the literature suggests that approximately 9% of patients developed these skin reactions and this is a contraindication given that there are alternatives to further usage of mitomycin C.
Mitoxzantrone
This agent is chemically related to doxorubicin and has been shown to be useful with relatively few installations in a phase II study. It has an effect equivalent to epirubicin or mitomycin but needs only half the number of installations. It is a useful second-line agent in patients who have persistent superficial disease, are intolerant of Bacille Calmette-Guerin or who find it burdensome to come and have intravesical installations on a weekly basis.
Valrubicin
This is a semi-synthetic analogue of the antibiotic Adriamycin. It is highly lipophilic and installations at a dose of 800 mg and 13.3% ethanol have shown good efficacy levels, as described by Newling et al.. Fifty-four per cent of patients had a complete response after six installations, confirmed by review cystoscopy at 3 months. This again is a useful second-line agent but has no proven benefits or superiority over the longer-established mitomycin C or epirubicin.