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Published on 1 June 2002

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Intravesical chemo to treat bladder cancer

Keith Baxby
BSc MB BS FRCS(Eng) FRCS(Ed)
Consultant Urological Surgeon
Tayside University Hospitals
UK
E:keith.baxby@tuht.scot.nhs.uk

The healthy bladder is lined with specialised waterproof transitional cells – 95% of bladder cancer is derived from such cells, hence it is a transitional cell carcinoma.

Known causes include exposure to aniline dyes and other substances previously used in industrial processes. The most common current risk factor is smoking.(1)

Bladder cancer usually presents as blood in the urine (haematuria), and the diagnosis is made by cystoscopy. Firstline treatment is endoscopic resection of the tumour. Histological examination shows one of three situations.

  • In 70% of cases the tumour will be noninvasive. Resection is curative, but there is a high risk of further tumours developing in the bladder, so the patient starts a programme of check cystoscopies at intervals for at least seven years.
  • About 25% of cases show invasion into the deeper layers of the bladder wall. Such patients cannot be cured by endoscopic resection and need radical surgery or radiotherapy.
  • Five per cent of cases will have carcinoma in situ, where the bladder epithelium contains highly abnormal malignant cells confined to the ­epithelial layer. This a dangerous disease that can progress directly to invasive tumour. Many patients would need radical surgery if it were not for the availability of intravesical chemotherapy.

Intravesical chemotherapy
Intravesical chemotherapy is used in three situations:

  • Where there are many (say, 10 or more) superficial tumours (see Figure 1) and resection would be impractical. A six-week course of intravesical chemotherapy reduces their number to ­manageable levels and can sometimes kill all the tumours.
  • As a single dose instilled after tumour resection to reduce the risk of recurrence.
  • For the treatment of carcinoma in situ (see Figure 2).

[[HPE04_fig1_51]]

[[HPE04_fig2_51]]

Although intravesical chemotherapy using agents such as thiotepa, ethoglucid and doxorubicin has been in use for many years, European practice is now almost entirely confined to the use of mitomycin C and of BCG (bacille Calmette–Guérin). Both agents are suitable for the first indication mentioned above; only mitomycin C for the second; and only BCG for the third.

Mitomycin C
Mitomycin C is an antitumour compound converted in the tissues to an alkylating agent that is cytotoxic (by disrupting DNA) and antimitotic (by preventing DNA synthesis). It must be made up under aseptic conditions and instilled into the bladder via a urinary catheter. The dose is usually 40mg in 40ml water. After reconstitution it should be used immediately. Contraindications are known hypersensitivity to the drug or an untreated urinary tract infection.

Mitomycin C for multiple superficial bladder tumours
Mitomycin C is given over six weeks, most commonly 40mg once a week. To reduce dilution of the drug by urine, patients avoid fluid intake for three hours and empty the bladder immediately before treatment. Patients taking daily diuretics delay the morning dose on the day of treatment.

After instillation of the drug the patient is asked to lie on their right side, left side, back and front for 20 minutes each to ensure complete coverage of the bladder. Side-effects are usually minor. The urine will be purple when the bladder is first emptied, owing to the colour of the drug. Many patients develop frequency of micturition due to bladder irritation for 48 hours after administration. This is eased by drinking copious amounts of fluids. Rarely, a systemic allergic reaction with skin rash will occur, preventing further treatment.

In 70% of patients there will be significant reduction in the number and size of tumours, and 30% of patients will have complete tumour clearance.

Mitomycin C for prophylaxis
A single dose of 40mg can be instilled into the bladder within 24 hours of tumour resection. The risk of subsequent tumour recurrence is reduced by 34%, and the recurrence rate per year by about 50%.(2) There is debate over whether mitomycin can reduce the risk of progression from superficial disease to invasive disease.

BCG (bacille Calmette–Guérin)
This live-attenuated strain of the causative organism of tuberculosis is the most effective treatment (other than radical surgery) for carcinoma in situ. For multiple superficial tumours it has a higher success rate than mitomycin C and reduces the risk of progression from superficial to invasive disease. However, the frequency and severity of side-effects is high, so for this problem mitomycin remains the drug of first choice for most urologists.

The action of BCG is associated with an intense inflammatory reaction in the bladder lining resulting in the accumulation of immune-competent cells.(3)

Because live bacilli are used there is a small risk of a systemic tuberculosis-like illness. Therefore the drug must not be used in patients with immunosuppression or those who have any febrile illness, and the patient must have been immunised (naturally or therapeutically) against tuberculosis. The most common contraindication is that the drug should not be used within two weeks of biopsy of the bladder or resection of a bladder tumour, since these leave a raw surface permeable to the bacilli.

The dose used provides between 3 and 9 x 10(8) colony forming units per instillation. The dose in mg to achieve this will depend on the commercial preparation used.

Administration
BCG must be reconstituted and used in a manner that gives protection to the pharmacist, nurse and patient. The pharmacist and nurse must wear a mask with eye protection, a disposable gown and sterile gloves. It is essential that catheterisation is atraumatic as severe systemic “BCG-osis” can occur if the urethral lining is damaged. However, the usual lubricants for catheters contain antiseptics and preservatives, which reduce the viability of the bacilli and compromise success.(4) The recommendation is to use no lubricant at all (females only) or catheters with a hydrophilic coating as used for clean intermittent self-catheterisation (males and females).

As with mitomycin, patients should withhold diuretics on the morning of treatment, restrict fluids for three hours before surgery, and pass urine immediately before treatment. They should then lie on their right and left sides and back and front for 15 minutes each and then try to hold on to the instillation for a further hour. When the bladder is first emptied a cup of household bleach should be poured into the toilet and left for 15 minutes before flushing. Men should sit down to pass urine for six hours after treatment to avoid spraying and contamination. Sexual intercourse is avoided for 24 hours, and a condom must be used for one week.

Side-effects and complications
Side-effects are common and occasionally very serious.(5) Seventy per cent of patients get mild fever, bladder irritation and flu-like symptoms for 24 hours after surgery. Paracetamol is helpful. If the fever is higher than 38.5(˚)C for more than 24 hours the patient should stop treatment and take isoniazid 300mg daily for three months. BCG treatment can be resumed when symptoms resolve. Allergic reactions producing a rash or muscle and joint pains should also be treated with isoniazid for six months, and BCG treatment should resume only if the benefits significantly outweigh the risks.(6)

Very few patients (less than 1%) develop “BCG-osis”, an acute severe illness with inflammation of the lungs, liver and kidneys. They need triple antituberculosis therapy (isoniazid, rifampicin and ethambutol) for six months and must have no further BCG. Very rarely an acute fulminating BCG sepsis occurs. As well as six months of triple therapy this may need urgent treatment with intravenous steroids.

Results
Eighty per cent of patients with carcinoma in situ respond, but half of these will relapse without further treatment. With further short (three-week) courses of BCG at three months, six months, 12 months and 24 months, about 65% remain disease-free.

Two-thirds of patients with multiple superficial tumours show a complete response, and at three years 80% of this two-thirds remain disease-free. Of patients who show a partial response and then have endoscopic resection of residual disease, two-thirds are disease-free at three years, compared with only one-third of those treated by resection alone.

Future developments
Improvements in BCG therapy are concentrated on reducing the dose while maintaining efficacy. New chemotherapeutic agents are under assessment (eg, valrubicin(7)) but are not in routine clinical use in Europe.

Conclusion
Intravesical chemotherapy with mitomycin C or BCG is a useful adjunct to standard endoscopic surgery. It can cure bladder cancer in some patients, and in others can reduce the time to recurrence and the risk of progression to invasive disease.

References

  1. Vineis P, Marlone T, Radone D. Molecular epidemiology of bladder cancer: known chemical causes of ­bladder cancer: occupation and ­smoking. Urologic Oncol 1995;1:137-42.
  2. Tolley DA, Parma MK, Brigor KM, et al. The effect of intravesical ­mitomycin C on recurrence of newly diagnosed superficial bladder cancer: a further report with 7 years of follow up. J Urol 1996;155:1233-8.
  3. Böhle A, Gerdes J, Ulmer AJ, Hofstetter AG, Flad HD. Effects of local bacille Calmette­–Guérin therapy in patients with bladder carcinoma on immunocompetent calls of the bladder wall. J Urol 1990;144:53-8.
  4. Böhle A. The effect of lubricants on viability of bacillus Calmette–Guérin for intravesical immunotherapy against bladder carcinoma. J Urol 1996;155:1892-6.
  5. Lamm DL. Complications of bacillus Calmette–Guérin immunotherapy. Urol Clin North Am 1992;19:565-72.
  6. Catalona WJ, Hudson MA, Gillen DP, Andriole L, Ratliff TL. Risks and ­benefits of repeated courses of ­intravesical bacillus Calmette–Guérin therapy for superficial bladder cancer. J Urol 1987;137:220-4.
  7. Randall S. Valrubicin: an alternative to radical cystectomy for carcinoma in situ of the bladder. Urol Nurs 2001;21:30-6.

Resources
Kyowa Hakko (manufacturers of ­mitomycin C)
European offices:
Kyowa Hakko Europe GmbH
Immermannstrasse-3
D-40210 Dusseldorf
Germany
T:+49 211 177280  F:+49 211 1772841
Kyowa Hakko UK Ltd
258 Bath Road
Slough
Berkshire SL1 4DX
UK
T:+44 (0)1753 566000
F:+44 (0)1753 566010
Kyowa Italiana Farmaceutici SRL
Viale Fulvio Testi 280
20126 Milano
Italy
T:+39 (0)2 6447041
F:+39 (0)2 64470444
Kyowa Hakko Kogyo Co. Ltd
Hungary Direct Commercial Representative Office
1st Floor
Bég utca. 3–5
H-1022 Budapest
Hungary
T:+36 1 2120645
F:+36 1 2120644

Forthcoming events
24–28 June 2002
British Association of Urological Surgeons (BAUS) Annual Meeting
Glasgow
Contact:
BAUS
35–43 Lincoln’s Inn Fields
London WC2A 3PE
T:+44 (0)20 74051390
F:+44 (0)20 74045048
E:admin@baus.org.uk
W:baus.org.uk
27–29 Nov 2002
BAUS Section of Oncology
5th Annual Meeting – Bladder Cancer
Bournemouth, UK
Contact:
Jane Morrison
BAUS
T:+44 (0)20 74051390
F:+44 (0)20 74045048
E:oncology@baus.org.uk



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