Non-invasive bladder cancer is common. Almost 80% of the tumours are
superficial at the time of first diagnosis whilst 70% recur and 10-20% of patients eventually show lesions of higher stage or grde. The challenge today is not the primary management of the tumour, nor the treatment of recurrences, unless these are multiple and very fre±uent, but rather the prevention of invasion.
Tumours develop over many years and the Urologist sees the end process of
initiating and promoting factors which have been at work for some time. Where there is a suspicion of occupational exposure, the patient may change his work but Urologists seem less clear about simple things such as advising the patients to stop smoking and of the true potential of intravesical chemotherapy. Over the last 15 years the Urological Group of the European Organisation for the
Research and Treatment of Cancer (EORTC) and the Medicel Research Council
(MRC) have investigated some 5,000 patients in a variety of studies using different forms of intravesical agents. The drugs most commonly used have included Adriamycin, Epodyl, Mitomycin C and Thiotepa. Each produces a 60% or more complete and partial remission rate when used for therapy and appears to halve the recurrence rate when used intensively (weekly for four weeks and monthly for 11 months) or by one thrid with a single instillation. The side-effects of the agents are shown in Table 1. Although the use of BCG has become increasingly common in recent years, there seems no evidence yet from randomised studies that it is superior to intravesical chemotherapy
DEVELOPMENT OF INVASIVE DISEASE
In the EORTC protocol, an increase in T category (over a relatively short period
of observation of 1-3 years) was seen in only 4% of primary tumours and 13% of recurrent tumours in Protocol 30751 Comparing Thiotepa, VM 26 and control and in 10- 12% of patients on Adriamycin, Epodyl or control in EORTC Protocol 30790, there being no difference between the groups receiving chemotherapy and the control arm (1, 2).
In a sub-set of patients treated in Yorkshire there was a suggestion that death
from invasive bladder cancer was higher in those on the control arm in Protocol 30751 (3). This was not reflected in the patients in the same study from Europę, possibly because further intravesical chemotherapy had been given to patients outside the UK.
In Protocol 30845, no difference was seen in recurrence rate between BCG
(RIVM) and Mitomycin C, but in EORTC Protocol 30863 a single instillation of
Epirubicin (80 mgs after TUR) was associated with a 30 % reduction on recurrence
rate. No data on invasion are yet available (4).
As the evidence built up, increasing interest was shown in the isolation of
Prognostic factors. In 1982 Schulman noted the importance of tumour recurrence,
size of tumour (> 3 cm), multiplicity of tumours and a high G category in determining outcome (5). Other studies have also shown the marked difference in outlook in T category between Ta and Tl where the progression rate was 5-10 times greater in the patients with category Tl disease whilst the survival was reduced by 25-50% at five years (6, 7).
THE WORK OF THE MRC UROLOGICAL GROUP
The MRC adopted a slightly different approach to that of the EORTC and in
two studies compared the use of a single instillation, five instillations at three-monthly intervals, or no additional treatment following trans-urethral resection of newly diagnosed non-invasive bladder tumour. The use of one or five instillations of Mitomycin showed a significant reduction in the recurrence rate (8). In this group the Prognostic factors were analysed in a different way by Dr Parmar who was able to find three groups of patients depending upon whether the tumour was single or multiple at diagnosis, and the appearances at the three-month cystoscopy. The three groups are seen in Table 2 and the recurrence rates following the use of Thiotepa or
Mitomycin C in Tables 3 and 4. Two-thirds of the patients fall into Group 1 whilst
the most difficult group contains only 6-10% of all patients (9). If one uses the three Prognostic groupings to determine the treatment given, it is obvious that less active therapy will be re±uired in Group 1 than in Group 3 which will contribute the majority of patients with troublesome recurrences and invasive bladder cancer. In addition the evidence from the work of these two urological groups has demonstrated that, except for the smali number of patients in Group 3
a. one instillation of an agent will reduce the recurrence rate by 30%.
b. serial treatment involving 5-15 instillations will reduce the recurrence rate
In the third group intravesical chemotherapy may or may not be adequate and
other treatment including systemic chemotherapy or cystectomy may be re±uired (U).
The evidence suggests that all patients, even those in Group 1, should be given
one instillation of intravesical chemotherapy after TUR and that the patients in
Group 2 should probably receive instillations three-monthly for one year, whilst in
Group 3, if intensive therapy given weekly or later monthly is not effective, early treytment by some other means should be considered. The implications of such an approach are largely financial since a single instillation of an expensive agent will be given to 60% of patients (with a good risk category who, in the majority of Hospitals, are probably not treated other than by TUR) and several instillations to the remainder.
We are currently exploring with other colleagues and with the managers of our
service at Regional level, the implications of adopting such an approach and the likely cost benefit analysis.