C A R C I N O M A OF T H E B L A D D E R :

I T S T R E A T M E N T BY S U P E R V O L T A G E X - R A Y T H E R A P Y

ROBERT MORRISON, M.D., F.R.C.P.(Ed.), F.R.C.S.(Ed.), F.F.R.

Medical Research Council Radiotherapeutic Research Unit, Hammersmith Hospital, London

DURING the past decade the advances in radio- therapy have considerably extended its scope in the treatment of certain types of malignant disease. This has been especially evident in cancer of the bladder, where progress has been made in two lines of treatment. First, with the in t roduct ion of artificial radioactive isotopes a number of techniques have been developed in which an isotope is im- planted into the bladder wall or is introduced in liquid form into the cavity of the organ to treat certain localised types of malignancy. Second, the development of supervoltage apparatus has pro- vided a means of treating more advanced tumours with doses of radiation which could not be given by 200-250 kV x-rays because of skin and other tissue reactions. The improved dose distribu- tion with supervoltage radiation permits a higher dose m be given to the tumour with relatively lower doses to the skin, pelvic bones and other normal tissues, and with a lower integral dose (Bewley et al 1959). Immediate reactions are therefore less severe, and better long-term results are to be expected than with former methods of deep x-ray therapy. It must be noted, however, that some of the more deeply seated normal tissues through which the beam passes receive high doses of radiation and the possibility of late effects which may take some months or years to develop has, therefore, to be borne in mind.

Preliminary reports on the treatment of bladder cancer by supervoltage radiation have already been published by Williams (1948) employing a one million volt plant and by Stapleton (1953) and Blomfield (1956) using the 2 MeV van de Graaf generator. Plank, G r o s s m a n and Campanella (1957) and Cuccia, Jones and Crigler (1958) have reported on cobalt-60 therapy and Swinney (1957) has given an account of treatment using the 4 MeV linear accelerator. These reports confirm the immediate clinical advantage of supervoltage therapy. The present report is based on the treat- ment of a series of 210 patients between 1954 and 1958 by an 8 million volt linear accelerator installed by the Medical Research Council at Hammersmi th Hospital.

FEATURES OF T H E DISEASE To plan treatment along rational lines it is worth

examining some of the features of the disease which may have a bearing on the treatment. Three of these with which we may be interested are: first, the behaviour of the tumour and its mode of spread; second, its sensitivity to radiation; and third, the effect which the tumour may have on bladder and kidney function.

1. The behaviour of bladder cancer and its spread.--In the development of many malignant growths we believe that two of the changes which characterise the malignant process, viz.: cellular proliferation and invasion of surrounding normal tissue, have their origin at about the same time and progress pari passu. In bladder cancer, however, these changes in the behaviour of the cell seem to develop in two stages which may extend over several months or years. In the initial period, cell proliferation takes place with the formation of tumours which are pedunculated or sessile, depend- ing on whether the effect is localised or diffuse. These tumours grow into the cavity of the bladder, forming large papillary or solid masses, but without any evidence of infiltration of the muscle coat; at this stage the condition may be regarded as a benign tumour. After a varying period of time invasive properties develop and tumour cells extend through the bladder wall to infiltrate the extravesical tissues.

At the proliferative stage, when there is little or no infiltration, the tumour is usually treated by local diathermy or by segmental resection of the affected region of the bladder if this is practicable, or by local radiotherapy. The radiation treatment of choice may be either an implantation to the bladder wall of radon seeds or tantalum wire for the more localised solitary growths, or the instilla- tion of radioactive fluid or the introduction of a solid central source for the more extensive super- ficial tumours. When the tumour has reached the invasive stage, treatment has to be by radical surgery or by external radiotherapy.

The local spread of the disease has been studied in specimens removed at operation. Baker (1955)

125

126 CLINICAL

ried to relate the circumferential spread o f the tumour in the bladder wall to the depth of in- filtration which had occurred. He found that when the tumour had extended to involve the muscle layer there was a marked tendency for a spread to occur around the bladder wall in the lymphatics and in the planes of the muscularis so that tumour cells were seeI1 at some distance f rom the primary growth. For example, when the tumour had extended half-way or more through the muscle the average amount of bladder circumference involved was 60 per cent; in only one case out of ten was less than one-third of the circumference affected. When the tumour has infiltrated the muscle layer, therefore, it would appear to be necessary to treat the whole bladder rather than to restrict the radiation to the section of bladder affected by macroscopic tumour only.

The work of Jewett and Strong (1946) on the distant dissemination of the tumour has some bearing on the plan for therapy and on the prog- nosis. In a study of 107 cases, they related the incidence of metastases to the depth of penetration of the growth into the bladder wall. When sub- mucosal infiltration only was present there were no metastases; when there was muscle infiltration, one out of fifteen showed a metastasis in a regional lymph node; but when there was extension to the perivesical tissue, fifty-two out of eighty-nine (59 per cent) had either lymphatic or blood-borne metastases or both. This greater tendency to disseminate from the perivesical area has been attributed to the wider and more numerous lym- phatic vessels which are present there. The implica- tions are that when tumours are still confined to the mucosal and muscle layers they are potentially curable by local treatment to the bladder, but if the perivesical region has become involved only about 40 per cent carl be cured by successful local therapy.

TABLE 1

RESPONSE OF TUMOUR 8 MeV 4,500-5,500 rads in four weeks

At cystoscopy

No tumour seen

Tumour smaller

No change

Tumour larger

No cystoscopy .

No. of patients

64 (31%)

35 (17%)

19 (9 %)

7

85 (43 %)

210

R A D I O L O G Y

With supervoltage radiation, larger volumes of tissue may be irradiated to higher dose levels, and for cases which have perivesical extension it is possible to include within the field of treatment the immediate areas of lymph node drainage and thus bring a greater proport ion of tumours into the potentially curable group.

2. Radiosensitivity of the turnout and chance of turnout ablation.--lt is generally agreed that bladder cancer has a limited degree of sensitivity to radia- tion and that even when high doses are given only some turnouts respond completely. In view of the many factors which affect the tumour sensitivity, it is difficult to express this precisely in terms of the radiation dose in a given time. A practical measure of tumour response may be expressed as the chance of tumour ablation at one or more dose levels for the different types of tumour. Observation of bladder tumours during treatment is not practicable, but a cystoscopy may be carried out some weeks after the end of treatment and from these observa- tions we may deduce something of the tumour response. Table 1 shows the response observed at cystoscopy between two and four months after a course of radiotherapy in the present series of patients treated by 8 million volt irradiation using the technique to be described later and with a tumour dose of f rom 4,500 to 5,500 rads in four weeks.

Unfortunately, 43 per cent of the patients were not fit for cystoscopy because of deterioration in their general health, but it seems likely that in them the tumour showed no response. At this dose level, therefore, 31 per cent of tumours underwent complete ablation and a further 17 per cent showed a partial response.

Table 2 shows the response of the tumours analysed according to the stage of advancement of the disease. The staging used is the clinical staging suggested by Wallace (1956).

It will be seen that the chance of tumour

TABLE 2

RESPONSE OF TUMOUR ACCORDING TO STAGE OF DISEASE

Stage

T1

T2

T3

T4

Number of patients

70

26

69

45

Regression

Tumour ] smaller

No tumour seen

30 (43 %)

8 (30 %)

15 (21%)

11 (24 %)

13 (19%)

i 3 (12%)

12 (17%)

7 (15%)

C A R C I N O M A OF THE B L A D D E R 127

regression is greatest in stage T1 ( tumour involving mucosa only), but that complete regression may also be obtained in the more advanced stages T3 and T4. The histological type of the tumour did not seem to affect the response appreciably; the greatest number of tumours were transitional cell c~,rcinomas and the number of squamous and anaplastic tumours was too small to show any difference in response. We may therefore conclude that at this dose level there is between a 21 per cent and a 43 per cent chance of obtaining complete turnout ablation according to the stage of advance- ment of the growth.

3. The effect of the turnout on bladder and kidneyfunction.--Any effect which the tumour may have on bladder or kidney function depends on its situation and its extent. As tumours commonly arise at the base of the bladder, the urethra and ureters often become involved. A bulky tumour at the base of the bladder may obstruct the ureter and cause difficulty with micturition. Involvement of the sphincter muscle by growth may be the cause of pain and strangury or dribbling in- continence. These symptoms are frequently made worse by infection and by radiation reaction. Ureteric obstruction causes hydro-ureter and hydronephrosis with increasing impairment of kidney function which, if bilateral, leads to the gradual onset of uraemia.

T R E A T M E N T T E C H N I Q U E In view of the tendency of the tumour to spread

around the bladder wall, as Baker (1955) observed, the whole organ was included in the field of ir- radiation. When there was no evidence of extra- vesical extension of the tumour as determined by rectal and bimanual examination only the bladder and a small surrounding margin of tissue were treated. When extravesical extension was palpable, larger fields were used so as to include within the

treated volume the whole of the anterior part of the pelvic cavity, including the extravesical tissues and the lymph nodes on the lateral pelvic wall. The fields were also extended upwards to include the nodes at the junction of the external and internal iliac veins and downwards to cover the prostate, which is frequently involved in tumours of the bladder base. Irradiation of the rectum was avoided as much as possible, but in practice this is difficult to achieve even with the sharply defined supervoltage beam. Measurements made by Dr T. J. Deeley showed that the anterior rectal wall received the full m m o u r dose when the larger field technique was used.

Treatment was given by a fixed field technique using the common arrangement of four obliquely directed fields as shown in Figure 1. An average field size for an intravesical tumour was 7 × 9 cm. For tumours which had spread outside the bladder the field size was about 10× 10 cm. Where the tumour involved the artterior bladder wall, a single central field was used in front.

In patients who had difficulty in lying prone on the treatment couch because of obesity or because of a suprapubic catheter, two anterior oblique fields only were used with wedge filters to give an even tumour dose (Fig. 2).

Patients were treated over a period of four weeks by daily treatments. In the technique for the intra- vesical tumours a mean dose of 5,500 rads was prescribed. Because of the larger volume treated in the extravesical tumour techniques, the mean tumour dose was reduced to 4,500 rads. I t was possible to give the full dose to all but fourteen out of 210 patients treated.

As there is a considerable individual variation in the position of the bladder and there is also some movement of the bladder within the pelvis in changing f rom the prone to the supine positions, particularly in the female, it was found necessary to

7 × 9 c m 2 7 × 9 c rn 2

FIG. 1 Isodose distribution in four field technique for intravesical FIG. 2

tumours. Isodose distribution in two field wedge filter technique.

128 C L I N I C A L R A D I O L O G Y

take radiographs of each field with opaque dye in the bladder in the treatment positions.

The patient lies on the treatment table with the pelvis supported by a perspex bridge. To ensure accurate positioning each day, mid-line points in the suprapubic and sacral regions are marked on the skin and the position of the patient is adjusted until one mark is vertically above the other as indicated by the front and back pointers of the machine. The couch is then moved until the front pointer is over the central point of the field to be treated and the tube head is rotated to the correct angle. The system of pivoting used on the linear accelerators by which the tube rotates around the skin entry-point of the beam or around the tumour greatly facilitates the setting-up of the oblique pelvic fields.

M A N A G E M E N T OF THE PATIENT D U R I N G T R E A T M E N T

A patient suffering from a carcinoma of the bladder may be debilitated by anaemia due to recurring attacks of haematuria, by infection in the urinary tract, and perhaps also by some impairment of kidney function. These complications have to be treated before starting the course of radiotherapy. The anaemia may be corrected by a blood trans- fusion and iron therapy, and an attempt should be made to control any infection by the appropriate sulphonamide or antibiotic drug. The bladder undergoing radiation treatment is very prone to infection with pyogenic organisms--a complication which increases the radiation reaction and requires prompt treatment. If the urine is uninfected at the onset of treatment, it is worth giving sulphonamides in reduced doses during the course of radiotherapy as a prophylactic measure. The long-acting low- dose sulphonamides (e.g., " M a d r i b o n " ) are particularly useful for this purpose.

In patients in whom there is severe impairment of kidney function due to ureteric involvement with a blood urea over 100 rag. per cent, it may be debatable whether the patient will benefit from radiation treatment at this stage. I f the turnout is not too extensive, however, and particularly in the younger patient, it is worth performing a pre- liminary nephrostomy, ureterostomy or ureteric transplant on the least affected side. If the kidney function recovers after the operation and the blood urea falls, the patient may be well able to undergo the full treatment. Mild cases of uraemia with a slightly raised blood urea may improve as the tumour regresses during treatment without any preliminary urinary drainage being required.

When the patient had dribbling incontinence from involvement of the bladder neck, a self- retaining catheter was inserted and the urine allowed to drain into a bottle beside the bed. It was sometimes possible to dispense with the catheter if control of micturition was regained during the treatment. If a suprapubic cystotomy had recently been performed and the wound was still draining urine, suction drainage per urethram using a Robert 's pump helped to keep the supra- pubic skin dry and allowed the fistula to heal more readily.

In view of the possibility of radiation effects on the small intestine and rectum a low residue diet was prescribed and the patient was advised to avoid any food which was normally liable to cause diarrhoea.

The symptoms which develop during treatment are due to the effect of the radiation on the bladder and also to the unavoidable irradiation of the rectum and of the lower coils of ileum which lie in the recto-vesical pouch. Irradiation of the bladder may cause increasing frequency of micturi- tion and some terminal dysuria, but if the symptoms are due solely to the radiation, they usually subside within a fortnight of finishing the course of treat- ment. Rectal reaction causes the patient to have a constant desire to evacuate the bowel, and there may also be a mucus discharge from the rectum. These complaints may be relieved by the use of hydrocortisone suppositories. If the small bowel is affected by the radiation the patient may have abdominal colic and diarrhoea and some tenderness may be elicited on palpation of the lower abdomen. This complication develops infrequently but may lead to severe dehydration. When it occurs the treatment course has to be interrupted until the symptoms abate.

The oedema which develops at the lower end of the ureters as a result of the radiation is said to predispose to urinary stasis and a tendency to ascending infection and pyelonephritis.

RESULTS OF T R E A T M E N T

The results of treatment will be considered under the following headings:

1. The relief of symptoms. 2. The effects on the bladder. 3. Survival.

Relief of symptoms.--Haematuria, which is the commonest symptom, is usually arrested during the third week of treatment, i.e., by the time the turnout has received 2,500 fads. Dysuria may also be relieved during the treatment.

CARCINOMA OF THE BLADDER 129

The effects of the treatment on the bladder. - -As a result of the radiation therapy a fibrinous reaction develops on the bladder mucosa which may take up to six months to disappear completely. Healing of the tumour area is associated with fibrosis and scarring, and sometimes with the formation of pseudo-diverticulae. As a result of the contraction of the fibrous tissue the bladder capacity may be reduced and the patient may have to void his urine very often. This disturbing complaint may gradually improve over a period of months as the remainder of the bladder distends. I f the symptoms persist and become incapacitating, a ureteric transplant operation may have to be considered.

Several months after treatment telangiectasia may develop; this is seen most commonly on the mucosa at the base of the bladder. I t may not cause any trouble, but occasionally one of the dilated vessels ruptures and the patient may suddenly develop alarming haematuria which may be difficult to stop. I f the bleeding continues over a prolonged period and cannot be fully controlled, a total cystectomy may have to be performed.

SurvivaL--There are no long term survival rates published yet for supervoltage therapy. The one- and two-year survival rates in the present series of 210 patients treated by eight million volt irradia- tion are shown in Table 3. These patients were treated solely by radiotherapy and had no previous surgery apart f rom surface diathermy in some cases. The tumours are broadly divided into those still confined to the b ladder- - the intravesical or stages T1 and T2- -and those that have extended outside the bladder-- the extravesical or stages T3 and T4- -as determined by bimanual examination.

The two-year survival rate of 35 per cent is similar to the results reported after total cystectomy by Whitmore and Marshall (1956) and by Wallace (1959). The patients suitable for cystectomy, how- ever, are a more highly selected group than those suitable for radiotherapy, which may be given to patients at a more advanced stage of the disease and in a condition unsuitable for surgery. A longer

TABLE 3

SURVIVAL RATES (Results calculated by life table method)

Intravesical (T1 and T2).

Extravesical (T3 and T4)

All patients .

No. of patients

96

114

210

One-year

64

43 %

53%

Two-year

44~

26700

35700

follow-up survey of the patients treated by super- voltage radiation is necessary, however, before reaching any conclusions about the relative merits of the two methods of treatment. Patients who are not cured by the radiotherapy may obtain relief of their symptoms for prolonged periods and the results will have to be assessed in terms of the length of time for which palliation is achieved as well as in cure rates.

SUMMARY

1. The advantages ofsupervoltage x-ray therapy in the treatment of bladder cancer are discussed and a report is presented on the treatment of a series of 210 patients by an 8 million volt linear accelerator.

2. The features of the disease which have a bearing on the treatment are reviewed. These include the behaviour and the spread of the tumour; its sensitivity to radiation and the chance of tumour ablation with the dose prescribed; and the effect of the tumour on the bladder and kidney function.

3. Details of the irradiation techniques used are described and the management of the patient undergoing the treatment is discussed.

4. The short-term results of the treatment are given. These are expressed in terms of sympto- matic relief, the effect of the radiation on bladder function, and the survival.

5. The one- and two-year survival rates are compared with the published survival rates after total cystectomy.

Acknowledgement.--I would like to thank my surgical and radiotherapy colleagues who have referred patients for treatment and who have kindly provided me with valuable information about the progress of their patients.

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BLOMEIELD, G. W. (1954). Brit. J. Urol. 26, 301. CUCCIA, C. A., JONES, S., ~; CRIGLER, C. M. (1958). J. Urol.

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