B.S. and T.M. are joint first authors as they contributed equally to the manuscript
Hannes Steiner, Urology, Medical University Innsbruck, Anichstrasse 35 Innsbruck 6020, Austria.e-mail: email@example.com
To report a prospective controlled study to compare the acceptance of two different ways of administering intravesical mitomycin C, as the immediate intravesical administration of chemotherapy after surgery decreases the risk of recurrence in patients with superficial bladder cancer, but response rates are variable, partly because of inadequate drug delivery and thus an adequate administration time is important for optimum oncological efficacy.
PATIENTS AND METHODS
Between October 2004 and June 2005, 60 patients were divided after transurethral resection of superficial bladder cancer into two groups. Both groups received an intravesical instillation of 40 mg mitomycin C diluted in 40 mL distilled water at ≤6 h after surgery. In group A the catheter was clamped; in group B the catheter was not clamped but the urine bag was elevated to 1 m above the level of the supine patient to enable bladder contractions with no rigid resistance, and mitomycin C was retained within the bladder by hydrostatic pressure. Discomfort and pain were documented by the patient every 15 min. The instillation was terminated after 2 h, or earlier if the pain was not tolerable. The relapse rate during the follow-up was also recorded.
Histology and the number of tumours resected was not significantly different between the groups. In group A the mean (sd, range) instillation time was 83.4 (3.1, 15–120) min and 11 (37%) patients tolerated all 120 min of treatment. The instillation time in group B was 110.4 (20.9, 60–120) min and 25 (83%) patients completed 120 min. The mean (sd) overall pain levels measured were significantly lower (P ≤ 0.05) in group B, at 2.7 (2.4) in group A and 1.8 (1.3) in group B. There was no remarkable difference between the groups in recurrence rates.
Elevation of the urine bag instead of clamping the catheter was associated with a significantly longer instillation, more patients completing the full 2 h of treatment and significantly lower pain sensations. There was no remarkable difference in the groups in recurrence rate during the follow-up, but this might be because there were few patients in this pilot study.
[Corrections made after online publication 6 August 2008]
Of patients with bladder cancer 70–80% initially present with superficial disease (stages Ta, T1 or carcinoma in situ, CIS). One instillation of chemotherapy after surgery (e.g. mitomycin C, epirubicin, thiotepa or pirarubicin) reduces the risk of recurrence, as shown in a recent meta-analysis . Subsequently, the European Association of Urology (EAU) guidelines  recommend one immediate intravesical instillation of a chemotherapeutic agent after transurethral resection (TUR) for all superficial bladder tumours (stages Ta, T1 or CIS), but there is still no recommended standardization of the method of instillation. For the maximum benefit, intravesical chemotherapy should be administered within 6 h after TUR . Reported response rates have been variable, partly because of inadequate drug delivery; it was concluded that an adequate administration time is important to achieve optimum oncological efficacy . In our experience, bladder contractions against the rigid resistance of intravesical fluid if the catheter system is closed leads to pain during the instillation, and subsequently lower patient acceptance. The rigid resistance might also be a reason for serious side-effects, such as bladder perforation after a deep resection, which was reported by different groups [4–6]. To avoid high pain levels and complications because of the rigid resistance of a clamped catheter we developed a simple way of retaining the chemotherapeutic agent in the bladder, and consecutively conducted a prospective controlled study to compare patient acceptance and instillation time of two different instillation methods of mitomycin C.
PATIENTS AND METHODS
Between October 2004 and June 2005, 60 patients were divided into two groups after TUR of suspected non-muscle-invasive bladder cancer (≤3 cm single or multiple, papillary, primary or recurrent tumour). Exclusion criteria were gross haematuria and suspected intraoperative bladder perforation.
Both groups received an intravesical instillation of 40 mg mitomycin C (Mito-extra®, Medac, Gesellschaft für klinische Spezialpräparate mbH, Hamburg, Germany) diluted in 40 mL distilled water at ≤6 h after surgery. In group A mitomycin C was instilled via a catheter and the catheter was clamped for 2 h (Fig. 1), as suggested by the EAU guidelines . In group B the catheter was not clamped but the urine bag was elevated 1 m above the level of the supine patient, to enable bladder contractions with no rigid resistance; mitomycin C was retained within the bladder by hydrostatic pressure (Fig. 2). Discomfort and pain were documented by the patient every 15 min on a visual analogue scale (VAS, range 1–10). The instillation was terminated after 2 h, or earlier if the pain was no longer tolerable. Routine pain medication after surgery consisted of hyoscine-N-butylbromide at the patients’ request. The duration of the instillation was documented after removing the mitomycin C and the urine volume was measured in both groups. Patients were followed at the outpatient department by cystoscopy and urine tests (dipstick, cytology).
The patients’ characteristics are shown in Table 1; the histology and number of resected tumours were not statistically different between the groups. Interestingly, there was no significant difference in pain sensations after surgery depending on the type of anaesthesia. In group A the mean (sd, range) instillation time was 83.4 (38.1, 15–120) min, vs 110.4 (20.9, 60–120) min in group B. The entire treatment period of 120 min was tolerated in 11 (37%) of group A patients vs 25 (83%) in group B.
Table 1. The patients’ characteristics
No. of patients
Mean (range) age, years
Overall pain levels (measured on the VAS) in group B were significantly lower (P < 0.05) than in group A, at 1.8 (1.3) and 2.7 (2.4), respectively; the difference was apparent after 15 min of treatment (Fig. 3).
The only reason for prematurely emptying the bladder was intolerable pain during the period of intravesical chemotherapy instillation. There were no complications after treatment in either group. The mean (sd) urine volume collected immediately after instillation was 315 (111) mL in group A and 373 (121) mL in group B.
After a mean (range) follow-up of 18 (3–33) months there was no significant difference between the groups in the recurrence rate (42% in group A vs 37% in group B).
According to EAU guidelines  the optimum treatment for low-risk solitary TaG1 lesions is complete TUR, followed by one instillation of a chemotherapeutic drug (mitomycin C, epirubicin or doxorubicin) within 6 h, the choice of the therapeutic drug being optional. In a meta-analysis, Sylvester et al. showed that one immediate instillation of intravesical chemotherapy after TUR decreases the recurrence rate in patients with single tumours, and in those with multiple tumours. However, these results indicated that one instillation is a suboptimal treatment for patients with multiple tumours, but is still recommended as an initial treatment. Barghi et al. reported, in a placebo-controlled study, that mitomycin C administered immediately after TUR led to a reduction in recurrence and increased the recurrence- free interval, in short-term results over 24 months.
Several different studies were reported on intravesical chemotherapy in patients with non-muscle-invasive bladder tumours; in these studies the catheter is usually clamped after the instillation for 1–2 h, or the catheter is removed. Serious discomfort is often reported by patients during intravesical therapy because of bladder spasms against the rigid resistance of the clamped catheter after mitomycin C instillation. However, the contact time should not be diminished; De Bruijn et al. reported that longer dwelling times are responsible for a significantly lower recurrence rate and cause fewer complications. Therefore, a full 2 h treatment would be desirable. In the present study there was no remarkable difference between the groups in recurrence rate during the follow-up, but this might be because there were relatively few patients in this pilot study.
The side-effects of intravesical mitomycin C instillation are mainly pain, but also chemical cystitis and contact dermatitis; allergic reactions have also been reported. Less common complications are reduced bladder capacity, bladder wall calcifications and myelosuppression due to high plasma levels . Case reports from Nieuwenhuijzen et al. and Racioppi et al. showed that severe complications of postoperative chemotherapeutic instillation are rare, but urologists using mitomycin C should be aware of the potential risks. In case of chemotherapeutic extravasation, the bladder pressure should be kept low by the catheter, which might be an argument for placing a catheter after TUR. If the pain persists after observation, Nieuwenhuijzen et al. suggested MRI to plan further treatment. Racioppi et al. even refrained from instilling mitomycin C if the surgeon detects thin spots within the bladder wall after TUR.
The present data suggest that by a simple manoeuvre (elevating the urine bag after instillation) the number of patients receiving the full 2 h of recommended mitomycin C dwell time can be increased significantly; bladder spasms that might cause pain and subsequently an unscheduled removal of the intravesical chemotherapy were experienced as being less painful. Elevation of the urine bag might be a precautionary measure not only for patients with a risk of severe side-effects, such as perforation because of spots of thin bladder wall, but also due to the lower pressure in case of bladder contractions. An additional advantage of the open drainage system vs the clamped catheter might be that major bleeding after TUR could be identified earlier.
For intermediate-risk tumours the guidelines  recommend TUR, and possibly re-TUR if complete resection was not achieved, and adjuvant intravesical chemotherapy or immunotherapy with BCG. Treatment recommendations for high-risk tumours are TUR, re-TUR after 4–6 weeks and after adjuvant intravesical immunotherapy with BCG, or radical cystectomy if there is no response to BCG therapy. However, repeat intravesical therapy for intermediate- and high-risk tumours is controversial. Lambert et al. analysed 104 patients with T1 high-grade tumours at the time of radical cystectomy; their study showed that over the last 15 years the disease-free survival of patients with high-grade T1 tumours has declined, and their data seem to indicate that the increasing use of intravesical therapies might be delaying curative surgery. However, there are no data available that one immediate intravesical application of mitomycin C after TUR could lead to a delay in curative treatment.
In conclusion, elevating the urine bag instead of clamping the catheter was associated with a significantly longer instillation time, more patients completing the entire treatment period, and significantly lower pain sensations. Whether longer dwelling times are responsible for significantly lower recurrence rates must be addressed in a larger series.