Bladder neoplasms—The challenge to the radiotherapist

CLINICAL THE

JOURNAL

OF

THE

• VOL. XIV

BLADDER

RADIOLOGY FACULTY

OF

RADIOLOGISTS

J A N U A R Y 1963

NEOPLASMS--THE

CHALLENGE

No. 1

TO THE

RADIOTHERAPIST*

F R A N K ELLIS, M.A., M.D., M.Sc., M.R.C.P., F.F.R.

Radiotherapy Department, United Oxford Hospitals, Oxford IN choosing my subject for this lecture I have been activated largely by the problems which have challenged me as a clinical radiotherapist. I hope, as a result of the work which I have been stimulated to do for it, I might be able to illuminate small corners of this problem, although I find that many authors have already directed a much more penetrating beam into all aspects of the subject than I am likely to be able to do. My aim for patients is "ease of body and peace of mind." We are concerned with people mostly old but some relatively young, who, after a first painless but alarming haematuria are subjected in most cases to a gradually increasing amount of distress due to instrumentation, surgical operation or treatment, associated with continued morbidity due to disease or to treatment. This causes pain, discomfort and misery due to a progressive burden of physical ill health, and social inadequacy, ending sometimes in a painful death from local disease or metastases, or culminating in a gradual deterioration of metabolism due to renal failure. To understand the condition it is desirable to

know something of many aspects, and I have considered carefully the notes on 234 cases, which I believe to comprise all referred to my department IOO~

@

ALL

BLADDER

NEOPLASMS

9c oc 7c

~ 6o ~ sc ~ ,o ~ 3o! 2c ,c

FROM

FROM I

R2,°:.A,

~

O

YEARS FIG.

2

Survival of bladder neoplasms from first symptoms and registration. too

CASES REFERRED

PAPILLOMA

80

TOTAL 1951- 1960 = 234

~:

40-

60

"6 ~30-

t

FROM MPTOM5 &

u

,,v 206

~ao

IO

20

:Z

IO

,o

r-

O

O

A

YEARS FIG. 1 Cases referred to the Oxford Radiotherapy Department, 1951-1960.

FIG. 3 Survival of patients with papilloma from first symptoms and registration.

*An abridged version of the Skinner Lecture given on 17th N o v e m b e r 1961, to the Faculty o f Radiologists A06 )

1

CLINICAL

RADIOLOGY

TABLE I BLADDER CARCINOMA,

SURVIVALS AT RISK

3 years From registration

Loo~

5 years

From symptoms From registration From symptoms

NO.

per cent

No.

per cent

No.

per cent

No.

per cent

Papilloma

23/33

70

29/34

85

15/27

56

26/32

81

Mucosa

11/27

41

22/26

85

4/25

i6

13/23

57

Muscle

7/36

20

24/40

60

3/35

9

11/37

30

Extravesical

1/27

4

5/24

21

0/27

0

0/24

0

Pelvic fixation with metastases

0/38

o

16/40

40

0/38

0

8/39

21

MUCOSA

•

{}

IOC

MUSCLE

7(

6o

6C

5o

sc

PDS.

>

>~ 4c

~o f 40

I1~1

~

3c

A~

-~ 2 0

R

•

4

o

---...._ O

i

i

I

2

i

i

3

4

o

~

;

4

5

Years

Y¢0rs

FIG. 5

FIG.4 Survival of patientswith tumoursinvolvingmucosa. WDS :well differentiated,survivalfrom symptoms. PDS =poorlydifferentiated,surv,:valfrom symptoms.

Survival of patients with tumours involving muscle,

W D R = w e l l differentiated, survival from registration. P D R = p o o r l y differentiated, survival from registration.

,oo[

EXTRAVESICAL

too

O

:

PELVIC FIXATION

9C

90 BC

8C

7O

7a

6c

~<6 0

sc

°z

50

K > 4o

e

tn

m 301 2c

.20 tO

Y¢ors,

FIG. 6

Survival of patients with extravesical extension of tumour.

/~

I

2

YEARS

3

4

FiG. 7 Survival of patients with pelvic fixation.

5

BLADDER

NEOPLASMS--THE

CHALLENGE

in Oxford in ten years from January 1951 to December 1960 inclusive (Fig. 1). The department was new in 1951 and apparatus inadequate. High energy beam radiation did not become possible until October 1958, when the first patient was treated on the 1,500 curie Cobalt unit. The development of the use of colloidal gold 198 solution for treating bladder papillomata caused interest among the Oxford surgeons and a consequent increase in the number of patients referred, which has continued as a result of the evidence elsewhere of the usefulness of external radiotherapy by high energy beams provided by the 2 MeV van de Graaf or the 4 MeV to 8 MeV linear accelerators. For most of the patients with whom I have been concerned, therefore, local methods and 250-300 kV deep x-rays only have been available. The results are poor according to the statistical analysis carried out, and are represented in Table 1, and in the graphs (Figs. 2 to 7).

TO T H E R A D I O T H E R A P I S T

,oc E SUMMATION X P O N E N T I A LOF TWO VES,

~ ~ g ¢

~ sc ~c 3c 2c Ib

2b

Fro. 8 Summation of two exponential curves (see text).

BLADDER NEOPLASMS AGE DISTRIBUTION ACCORDING TO SEX.

ANALYSIS OF CASES For the purpose of analysis, the cases have been divided into the clinical stages adopted as the Institute of Urology classification, namely: invasion of (1) mucosa only, (2) muscle, (3) perivesical tissues, (4) pelvic wall fixation. Histologically, although the diagnoses of papilloma, transitional cell carcinoma, squamous cell carcinoma, adeno-carcinoma, anaplastic carcinoma and leimyosarcoma have all been made, the numbers are too small for so many divisions to be profitable, and the analysis has been made under the headings '" well differentiated " and " poorly differentiated" only. The former includes those labelled Broders I and II, or moderately differentiated carcinoma. The papilloma group includes all those with an initial diagnosis of papilloma clinically or histologically at the time of registration for radiotherapy, although some of these subsequently were shown to have developed histologically malignant characters. When in doubt as to the degree or extent clinically, a case has been given the lower rather than the higher stage, e.g., mucosal rather than muscle. The graphs all show two kinds of survival curves: one from the beginning of symptoms, and the other from the date of registration in the radiotherapy department. In most cases the time of beginning of symptoms is very little different from the time of seeing the surgeon who subsequently referred the patient. At least 60 per cent of the patients had been treated in many cases for long periods before they came to the radiotherapy department. The difference in shape of the curves in each of the

I's MONTHS

2O ,s O/o

L_2

~ /

MEN

i~ r

,~ j-

_ _ _ _

o ~_~-

--

j )~ !~

.FE

- - - TO .T.B ..

~

..... O~RB. -,

i

~,~-2

~.~

O

S

O/o

:

r-

~o

20

FIG. 9 Age distribution according to sex of patients with bladder neoplasms. Full line, Churchill Hospital series; dotted line Oxford regional board series; broken line T.O.T.B. ( = T u m o u r s of the Bladder: Wallace) series.

malignant categories stimulated my curiosity and I found that by combining two exponential curves, one starting later than the other, as indicated in Figure 8, a curve of similar shape could be obtained to that of the one for survival from the beginning of symptoms. This might imply, as we might infer from clinical experience, that there are two types of growth--one of which is malignant from the start of the symptoms, while the other is benign at first. The survivals as estimated from the date of registration, which is almost the date of beginning of radiation treatment, compare favourably with those published by other authors.

4

CLINICAL

For instance, Wallace gives a 46 per cent threeyear survival rate, and a 40 per cent five-year survival rate for all cases from the date of registration: the comparable figures for our cases are 26 per cent and 15 per cent respectively, but from the date of beginning symptoms, 57 per cent and 38 per cent (Table 1). Mr Wallace's figures are those of a urological surgeon working with a radiotherapy department, and it seems that they will refer patients somewhat earlier in the disease than those referred to me, but later, of course, than the time when patients first develop symptoms. The age and sex incidence also offer a clue to the discrepancy in results if, as will be indicated later, these factors affect prognosis (Fig. 9). The sex ratio of 1 w o m a n : 4-2 men is similar to that of Wallace, though the ratio for the papilloma cases, i.e., 1:4.6, implies a slightly higher proportion of men referred with papilloma than with carcinoma. The Registrar-General's figures for 1956 show a male-to-female sex ratio of 2003:833 --2.4, and the Oxford Regional Survey, a ratio of 501 : 193 for the years 1952 to 1957, - 2 . 6 . The age at reference is consistently higher than for Wallace's series, which in turn is higher than in the case of the patients in the Oxford Regional Cancer Survey. This latter represents as nearly as possible a true

RADIOLOGY TABLE 2 CANCER OF BLADDER--OxFoRD CANCER REGISTRY Percentage ( ± standard errors) of cases classified as late primary Age group (years)

Males

Females

Difference (F to M)

Under 50 50 to 60 60 to 70 70 to 80 over 80

42.1 51.7 59-4 57.9 54.6

72.7 65.2 80.4 67.8 78.3

30.6 13.5 21'0 9-9 13.7

Under 60 over 60

48.8 59.6

67.6 73.0

18"8 13"4

Difference

10'8

5.4

--

Bold figures indicate significant difference.

sample of the population in the region. Cases are included only if the domicile is in the region, and if they are considered clinically malignant. Cases diagnosed as papilloma are not included. This survey has been useful, therefore, in providing information on some points which refer generally to patients at a stage earlier than m y radiotherapy cases, since the information is supplied

TABLE 3 CANCER OF BLADDER--OxFORD CANCER REGISTRY DURATION OF SYMPTOMS BEFOREPRESENTING Duration of symptoms Total Sex

Under 14 days No. per cent

21 to 6½ months

6½ months to' 2½ years

Over 2½ years

No. per cent

No. per cent

No. per cent

No. per cent

14 days to 2½months No. per cent

N ot stated No. per cent

Male

77

15

114

23

110

22

96

19

38

8

66

13

501

100

Female

28

14

32

16

45

22

37

19

17

9

34

17

193

100

TABLE 4 CANCER OF BLADDER--OxFORD CANCER REGISTRY DURATION OF SYMPTOMS RELATED TO FIVE-YEAR SURVIVAL Duration of symptoms in weeks Sex

I Under 2 No.

per cent

2 to 10 No.

28 to 130

10 to 28

per cent

No.

per cent

No.

per cent

Over 130 No.

per cent

N ot stated or found clinically No.

per cent

Male

8/52

15

12/76

16

14/66

21

14/56

25

2/22

9

13/46

28

Female

3/17

18

3/21

14

5]38

13

4/21

19

5/13

33

5/16

31

11/69

16

15/97

15

19/104

18

18/77

23

7/35

20

18/62

29

Both sexes

C H A L L E N G E TO T H E R A D I O T H E R A P I S T

BLADDER NEOPLASMS--THE

by all the hospital surgeons in the region who see the patients first. The series includes the radiotherapy cases. The classifications are different, however, being based on the early and late staging, 1'00

60

o/o

40

EARLY

2O

LATE ;

o

I

2

I

I

YEARS

FIG. 10 Oxford Cancer Registry. Five-year survival curves for cancer of the bladder. TABLE 5

started by the NationalRadium Commission. The age incidence graph (Fig. 9) shows that the regional figures have a similar peak incidence to Wallace's cases. The proportion of late cases among female patients is significantlyhigher than among males (Table 2). This suggests to me that since vaginal examination makes more accurate staging possible in the females, male cases might be consistently understaged. There is no essential difference in pattern between males and females in the duration of symptoms before being registered in the survey (Table 3). In considering the effect of duration of symptoms on survival, however, it seems that longer duration of symptoms does not reduce appreciably the length of survival, implying that the more malignant types have symptoms earlier (Table 4). The expected better survival in early cases than in late is indicated by Figure 10 and three- and fiveyear survival figures are similar to Wallace's, and to the radiotherapy figures, if reckoned from the beginning of symptoms. The graphs of survival of early cases however, compared for males and females, show that the female cases survive better (Fig. 11).

CANCER OF BLADDER--OXFORD CANCER REGISTRY FIVE-YEAR SURVIVAL RELATED TO HISTOLOGY

I00

8C

Females

Males Histology No. of cases Squamous

Survivors per cent

No. of cases

Survivors per cent

9

11

-Y-0 -57-o

Transitional

76

26

19

42

Unqualified

88

28

35

26

None

114

12

58

12

Other

10

10

5

20

126

O0

o/~

•

FEMALE MALE

20 I

0

Total

50

40 ~

1'

I

!

!

2 3 4

i

5

YEAR~

"FIG. 11 Oxford Cancer Registry. Five-year sulwival curves for cancer of the bladder.

20

TABLE 6 CANCER OF BLADDER---OXFORD CANCER REGISTRY STAGE BY DURATION OF SYMPTOMS

Duration of symptoms Proportion of early cases in the total numbers Sex

Male Female Both sexes

Under 2 weeks

2 weeks to .2~- .months . . .

.

2½ to 6½ . months . . .

6½ months to 2½ years

Over 2½ years

Not stated or found clinically

No,

per cent

No.

per cent /

No.

per cent /

No.

per cent

No.

per cent

No.

per cent

43/77

57

43/114

38

33/110

30

42/96

44

13/38

34

20/66

30

6/28

21

9/32

29

13/45

29

10/37

27

5/17

29

7/34

21

49/105

47

52/146

35

46/155

30

52/133

39

18/55

33

27/100

27

CLINICAL RADIOLOGY

preponderance of cases staged as early in males. There is relatively L little variation of the proportions 90 of very short duration in males, to Bo whom, naturally, haematuria seems 7o to be more of an event than in the case of women. The cumulative 6o _1 graph (Fig. 12) shows surprisingly EARLY g so LATE little difference in duration according "6 40 to stage. Comparison of the histology with stage (Table 7), indicates that "~ 30 besides" there being more transitional 20 cell cancers than squamous, they have a higher incidence in the early than the late stages. Moreover, as one o 20 25 a'o would expect, there are more cases without histology in the late than Dvrcltion of symptoms Crnonths'~ in the early cases. The cumulative F~G. 12 Cumulative distribution curves for duration of symptoms according to stage. distribution curve (Fig. 13) shows that squamous cancers develop Oxford regional board series. symptoms earliest. The implication is that the early group in males conFrom Table 8 it is clear that the five-year survival tains more advanced cases than in females, support- of cases treated by surgery is much better than that ing the suggestion already made that staging of of those treated by radiotherapy, the results from females can be more accurate. Comparing survival surgery plus radiotherapy being intermediate. But with histology (Table 5), we find that patients with it is clear that surgery is used more for the early transitional cell carcinomata appear to survive better cases, and radiotherapy for the late cases, while of than those with squamous carcinomata, that there 35 per cent receiving no treatment at all, none are more transitional than squamous carcinomata, survived five years. and that survival of females with transitional cell Table 9 relates the type of treatment carried out tumours is relatively higher than for males. These to the histology and to the survival, and indicates, figures are not, however, statistically significant. in addition to the previously noted superior incidWhen we compare the proportion of early cases ence and survival of transitional cell carcinoma, in males and females (Table 6) according to the that there has been no real difference in treatment duration of symptoms, we find the same relative pattern for the patients with known histology, although there is a great number with " no histolTABLE 7 ogy " among the non-surgical cases. Finally, from the Regional Cancer Survey, we see that there is CANCER OF BLADDER--OXFORD CANCER REGISTRY STAGE BY HISTOLOGY considerable difference in survival according to age. The figures suggest that the change in prognosis might be most marked after the age of sixty, and so Early Late the graph shown in Figure 14 was constructed. The difference is clearly shown and may be important in Histology Ma'e Fc male / Male Female connection with my radiotherapy group of cases where the peak occurs after sixty-five in men and after seventy-five in women (see Fig. 9). The use of Squamous 16 8 / 2 4 / 23 8 / 13 10 the foregoing analysis in this paper has been to provide a background of a true sample of the population Transitional against which to assess other results. The results Unqualified in my radiotherapy group are worse. The staging of the radiotherapy group is often clinical, and None 48 24 15 32 /127 45 / 69 51 subject to more errors. As already mentioned, Other 6 3 - - - - I 11 4 I_ 3 2 doubtful cases have been understaged rather than Total 199 9T- 0T-[-$7g561£0- overstaged. The point which worries me is whether or not the treatment has been poor.

i,o

BLADDER

NEOPLASMS--THE

CHALLENGE

TO T H E R A D I O T H E R A P I S T

I00 90

IOO

80

gO 60 % ~

70. .c:

60.

uJ u

SO' 40'

tl

SQUAMOUS

•

TRANSITIONAL

X

UNQUALIFIED

0

4O

'w

30" 20

AGE~6o

20

I0' a.

i

0

5

-- ,

i

i

,O

15

Duration

of

2;

215

i

310~

symptoms ~onths)

~

; 4 ;

YEARS

FIG. 14 Oxford Cancer Registry. Five-year survival curves for cancer of the bladder.

FIG. 13 Cumulative distribution curves for duration of symptoms with histology.

TABLE 8 C A N C E R OF B L A D D E R - - O x F o R D

CANCER REGISTRY

S T A G E A N D T R E A T M E N T RELATED T O F I V E - Y E A R S U R V I V A L

Treatment No. of cases Stage

Sex

Surgery No.

per cent

No.

per cent

No treatment (inc. palliative) No.

per cent

No.

per cent

64"7

19

9.5

27

13.4

25

12.4

201 *

100

32

65.3

8

16'3

4

8"2

5

10.2

49

100

162

64"8

27

10.8

31

12"4

30

12.0

250

100

Male

72

25.4

90

31.7

29

10.2

93

32.7

284 *

I00

Female

36

25'9

36

25.9

9

6.5

58

41.7

139

100

108

25.6

126

29.8

38

9.0

151

35.6

423

100

Female Both sexes

Late

No.

Surgery and Radiotherapy

130

Male Early

per cent

Radiotherapy

Both sexes Five-year survival

31.5 per ceut

20.2 per cent

26.2 per cent

0 per cent

• One case incomplete

P R I N C I P L E S OF T R E A T M E N T BY R A D I A T I O N The principles followed in treatment have been as follows: 1. To treat the whole bladder mucosa for extensive mucous membrane involvement but to try to avoid treating the whole thickness of the bladder wall to too high a dose, so as to diminish the risk of a contracted bladder. 2. To treat local lesions by local radioactive sources, often in association with external radiation so as to smooth out the inequalities of dose due to an implant.

3. To use external radiation up to tolerance dose of normal tissues. M E T H O D S OF E X T E R N A L R A D I A T I O N The methods of external radiation by conventional x-rays aimed to give a uniform dose to the volume treated using multiple field or paraxial conical rotation and achieving a dose of about 4,000 rads in four weeks. With the Cobalt beam we have given 2,500 rads in two weeks palliatively, and 5,500 to 6,000 rads in six to eight weeks or 5,000 rads in three weeks, treating mostly three times a week. Occasionally, for curable cases when the

CLINICAL

RADIOLOGY

TABLE 9 CANCER OF BLADDER--OXFORD CANCER REGISTRY HISTOLOGy AND TREATMENTRELATEDTO FIVE-YEAR SURVIVAL

Treatment No. of cases Histology

Surgery No.

No histology Squamous Transitional

per cent

38

14-3

Radiotherapy

Surgery and radiotherapy

No treatment (inc. palliative)

No.

per cent

No.

No.

84

31'6

13

per cent 4.9

131

per cent 49"2

I

No.

per cent

266

per cent

100

27

49-1

13

23"6

9

16.4

6

10.9

"55

100

110

60.4

34

18"7

26

14.3

12

6"6

182

100

11

55-0

2

10'0

4

3

20.0

15.0

20

F.

16.0 12.8

M. F.

10.0 20.0

M. F.

30.1 37.8

M.

5.9

M.

I

Anaplastic

5-year survival

J

100

F.

Unqualified

86

54.1

22

13'8

19

12.0

32

20'1

159

M. F.

100

30.6 23 "4

I TABLE 10 BLADDER CARCINOMA--RADIOTHERAPY QUESTIONNAIRE EXTERNAL RADIATION

Centre

Ox.

Type

Field size era.

No. of Fields

Dose in rads.

Dose/ Session

Sessions/ total days

Equivalent dose in one month (rads.)

Cobalt

7X7 to 8X 12

Rotation

5,000 to 6,000

250 to 300

20/26

6,000

L.A.

15X 18

4to 6

6,500

150 to 200

35/49

5,850

L.A.

6X8

3

6,500

433

15/21

6,875

8X 10

3

6,000

400

15/21

6,300

Cobalt

8X10

4

6,000

240

25/28

6,000

Cobalt

8X8

3

6,000

200

30/42

5,400

300 kV. 3 mm.Cu.

8X 10

5

400 to 500

170

30/42

4,500

L.A.

8x8 lOx 10

3 3

5,000 2,000

340 2,000

15/21 1/1

5,250

Cobalt

8X 10

3

5,500 to 6,000

330

18 to 21 42 to 49

5,100

Cobalt

10 to 15 cm. (palliative)

3

2,500

420

6/14

300 kV. 2 mm.Cu.

8×10

6

4,000

310

13/28

turnout has been in the anterior half of the bladder, and for hopeless extensions anteriorly, 300 kV with a single anterior grid field may give remarkably good results, giving about 4,000 fads at the deepest part of the tumour. The results of a questionnaire

4,000

sent to some prominent radiotherapists are shown in Table 10, together with an estimated equivalent dose in one month. Our doses seem to be low, but we have to treat most of our cases three times, instead of five times, weekly.

BLADDER

NEOPLASMS--THE

CHALLENGE

I 0 0 °/o 8 x 8 cm

8x8c I 0 0 o,

K8cm DO%

Post. fields ot 120 °

8o% 8 x 8 cm.

TO T H E R A D I O T H E R A P I S T

might be possible to treat the bladder cases with two right-angled wedged fields, using one in the perineum anterior to the anus, and the other anteriorly. The isodoses using Cobalt 60 are shown to be doubtfully useful, but if a linear accelerator can be used, the distribution in the depth will be more practicable (Fig. 16), assuming that it is necessary to penetrate to a maximum of 12 cm. from the skin over the ischial tuberosities. The jig which we have had made to permit precise application of the treatment, using applicators with two blades to keep the patient and beam constant relative to each other, and utilising the skin sparing effect, is shown in Figure 17. Important features of treatment by external radiation are the complications. Radiation sickness is less troublesome than diarrhoea, or frequency 4 McV LINEAR ACCELERATOR OffsGt. 4cm 8din WE DGE

Post. fields ot I 0 0 °

FIG. 15 Isodose distributions with Cobalt 60 unit for treatment of bladder tumours.

Bladder cases are rarely treated now by less than FIG. 16 2 MeV or Cobalt 60 gamma ray beam. The patient lsodose distribution for wedge pair on 4 MeV linear accelerator. is cystoscoped, with the surgeon if possible, but alone if not, since I consider it essential and reasonable that the radiotherapist ............................................ should s e e w h a t he has to dealwith. ~;i~;2¢) : A catheter is left in position for a cystogram to be done, and a plan of treatment is suggested. Antero-posterior and lateral radiographs are made to show the position of the bladder relative to opaque skin markers. It is interesting to know the change in shape of the bladder as it becomes more empty, and so a series of radiographs were taken to show this. As expected, the bladder shrinks down to the region of the bladder neck just behind the symphysis pubis. From the cystogram the desired size and position of fields are determined, and an isodose distribution produced. The ones shown in Figure 15 are FIG. 17 typical. It has occurred to me that it Jig for positioning treatment fields for irradiation of bladder tumours.

10

CLINICAL

BLADDER ; TREATMENT WITH 6Ocm S.S.D. COBALT UNIT PATIENT SUPINE~ ~ 8 . . . . dg~ at 35° S

"~260

fads

applied

IOO~.j///

SCALE

O

5

IO

P5

20 cm

FIG. 18 T r e a t m e n t p l a n f o r b l a d d e r t u m o u r s i n v o l v i n g n o p o s t e r i o r field.

and pain on micturition. One may try to plan the treatment to avoid the rectum and bowel as much as possible by different arrangements, or small fields. Figure 18 shows a method of planning (a) to avoid turning the patient over, and (b) to reduce the amount of rectum treated. In planning treatment, unless both opaque medium and air are used for cystograms, it is impossible to see the whole bladder in the x-ray, and an apparent shift of opaque medium may be due to both shift of the bladder and to movement of the barium inside the bladder. This can give a false impression of a much greater shift of the bladder than actually occurs (e.g., as much as 9 cm. instead of 3 cm.). I f the patient is to be treated both prone and supine, this difference in position must be known, for accurate treatment. Only when the tumour is near the internal meatus, or in the hopeless stage of pelvic fixation, can the tumour be expected to keep its position relative to the bony pelvis when the patient turns over. It is our practice, as with others, to treat the patients with the bladder empty. We have found that cystitis and diarrhoea are the most common complications interfering with treatment. The former usually means an exacerbation of infection, and may be treated by antibiotic drugs after bacterial sensitivity has been determined, or by sulphonamides or Furadantin before this. The system used in Manchester of trying to ensure freed o m from infection before treatment starts should probably be followed. Diarrhoea may start early in treatment especially if large fields are used. A kaolin and opium mixture is the best remedy, but sometimes treatment has to be interrupted. Local radioactive sourees.--I have used radon seeds, radium needles, radioactive gold grains, and

RADIOLOGY

radioactive tantalum wire for local intravesical implantation in an attempt to achieve precision. Much depends on the exposure provided, and this depends on the patient and the surgeon. The use of tantalum wire contained in nylon tubing, and introduced from outside the bladder into its wall using long hollow needles, with the bladder open, seems most satisfactory to me, though the number of cases suitable for such local treatment is small. The five-year survival in eighteen cases treated by implantation, excluding one lost to follow-up, is 47 per cent, and the threetyear survival of twenty-five cases, excluding the same one, is 58 per cent. In many cases other methods supplement the implantation. Doses aimed at might be about 5,000 rads locally, with 4,000 rads given to the whole bladder by other methods. In the case of the few female patients with growths confined to the posterior wall of the bladder, treatment as for carcinoma of the cervix has been used. Out of twelve patients in whom this method was used, nine had growths classed as mucosal or muscular invasion, two of whom are alive six and seven years after. This represents about 30 per cent five-year survival of seven cases treated more than five years ago, but two others treated in 1959 are clear oftumour. In some of these cases t h e " cervix " r a d i u m was used as a supplement to external radiation for extensive tumours. The intracavitary methods used have varied according to the purpose envisaged. Intra-eavitary Methods.--As long ago as 1944, I conceived the plan.of trying to decide by killing freefloating cells by radiation to what extent multiple recurrences on the bladder wall after surgical treatment were due to implantation of cells or to a neoplastic tendency of the bladder mucosa. The only suitable way of trying to do this at the time was by the use of Thorium X solution. This is virtually an alpha particle emitter only, and we had an interesting time investigating its possibilities. It was found to stick to debris in the bladder, and even to the glass of the bottle in which it came, but after we had overcome these difficulties we found that it resulted in some cases in the disappearances of multiple tiny papillomata. This was an indication that it could be useful for preventing implantation of growths in the bladder, but in an attempted wider investigation, due to lack of comprehension of the principles involved, it was badly used, and for many unsuitable cases. When artificial radioisotopes became available, the further possibilities intrigued me. For a patient with a bladder wall literally filled with " seaweed " papillomata the possibility of using beta radiation

BLADDER

NEOPLASMS--THE

CHALLENGE

from radioactive colloidal gold free in the bladder to irradiate each papilloma on all sides occurred to me. After preliminary investigations to ensure safety, carried out with my physicist colleague Mr Oliver, I treated a patient with astounding success. Except where the Foley catheter balloon protected the neck of the bladder, all the papillomata disappeared. Local g a m m a ray treatment with intra-cavitary radium was used at the neck of the bladder, and he is still free of bladder disease nine years later at the age of seventy-six, having had a carcinoma of the rectum removed three years ago. The cases for which the method is really suitable as the main treatment are very few, and even then are not necessarily radio-sensitive. The beta radiation from yttrium 90 gives a better penetration. I consider the method of an intravesical solution still has its uses : - (a) As a primary treatment in suitable cases with multiple fronded or possibly small sessile papillomata. (b) To discourage seeding implantation of carcinoma cells by its use before open operation, or after closed diathermy. (c) To stop haematuria. (d) To deal with multiple tiny papillomata, leaving larger tumours to be dealt with by other means.

TO T H E R A D I O T H E R A P I S T

11

have had even larger doses supplemented by other radiation methods remain well. In general, from my cystoscopic observations, I would say that two applications of 300 mc., with one month interval should be enough to produce the maximum desired effect. The method is suitable for some cases of papilloma only, and some patients sent clinically as papillomata may be really carcinoma. Twenty-one cases treated primarily or only with 198Au are alive and most of them symptom free. Of fourteen patients who have died, seven died from causes other than the bladder disease. Other forms of intra-cavitary treatment have been used. The difference between treating a thick tumour and a condition ofthebladder mucosais made obvious by dosage considerations (Table 11). It is not generally realised how small are the depths from the surface of the various layers of the bladder wall. They are, approximately, epithelium 0.1 mm., mucosa 0.3 mm., submucosa 0.5 mm., and muscle 8 mm. Other methods which we have used are a central cobalt bead source, and radium ovoids into the bladder. For both of these the bladder must be opened. The fall of dose with depth of all these must be such that they are bound to underdose the deepest part of a tumour of any appreciable bulk, or to overdose the normalbladdermucosa. Theintracavitary radiation may, however, be used as part of a two plane irradiation, in which the other plane is an implant or, say, radium in the vagina and uterus. In using the central cobalt bead method, we avoided complications by limiting the dose with the bead to 4,000 rads, supplemented with 3,000 rads

A pure gamma radiator in solution could possibly be used for early carcinomata, but the only possibility is a very costly isotope of manganese produced in a cyclotron. Radiogold and yttrium leave the submucosa and muscle virtually untouched and thus treat only the diseased tissue. It has effects on the bladder mucosa which, if it is used in addition to other TABLE 11 methods, may result in an inDOSE AT DEPTH IN BLADDER WALL FOR 1,000 RADS TO SURFACE creased tendency to late ecchyI Depth below i moses. The doses received by 0oy 198Au 60Co Bead 60Co Rosary Part surface the bladder mucosa, if 300 mc. in 100 c.c. are introduced in a 0'l mm. 730 995 960 Epithelium 920 patient starved of fluid for about 985 920 Mucosa 0.3 mm. 5O0 8O0 nine hours and left for about three hours, is likely to be about 970 880 Submucosa 0.5 mm. 320 650 2,500 to 2,700 rads. In one man 660 360 Muscle 8.0 r a m . 45 ! 45 of forty who had a total of 7,400 605/1,000 300/300 Wumour 1 cm. in/out* 40/65 20/20 in three doses in four months, l was informed from St Philip's 405/1,000 170/170 2 cm. in/out* 24/30 0 Hospital that total cystectomy 290/1,000 100/100 18/20 3 cm. in/out* 0 was performed in April 1959, three-and-a-half years later, for 198Au and 90y for spherical bladder vol. 100 ml., radius 2-9 cm. radiation cystitis, but have been 60Co bead for spherical bladder vol, 180 hal., radius 3.5 cm. able to get no further informa6oCo rosary for spherical bladder vol. 24 ml., radius 1.8 cm. tion since. Other patients who * i n = d e e p to wail; out--projecting into lumen

12

CLINICAL

RADIOLOGY

TABLE 12 TOTAL CYSTECTOMY FOR RESIDUAL GROWTH

Subject

Age

F, B.

53

Sq. Ca. infiltrating

F.J.

46

Ca. infiltrating

J.W.

51

A.K. GoF.

Time of cystectomy after treatment

Found

Reason referred

Result after cystectomy

Papilloma (Sq. Ca.)

Well 3 yrs.

1 yr. 1 mth.

Ca.

Died 0-7 mths.

No Ca.

1 yr. 1 mth.

Ree. Ca.

Well 6 yrs.

76

Rec. Ca.

1 yr. 1 mth.

Papilloma

Died 12 days

58

Ca.

Papilloma (Grade I Ca.)

1 yr. 2 mths. Uraemia

9 yrs.

0-3 mths.

Type of treatment

m

TOTAL CYSTECTOMY FOR BLEEDING

A, W,

70

Papillomata

I yr. 6 mths.

Extraves. Ca.

Dying of metastases

Y×3 Co 3100/8

E.S.

70

Rec. papillomata

2 yrs. 9 mths.

Papillomata

Well 3 yrs.

CoBe 7000

P. N. B.

61

No epithelium No carcinoma

Died of operation

6000/

Rec. papillomata (tr. cell) Grade

0-11 mths.

I

S. J. H.

64

Rec. papillomata

0-6 mths.

7 weeks 5740/ 6 weeks

Ca. + chronic inflam.

TOTAL CYSTECTOMY FOR RADIONECROSIS--RADIAT1ON CYSTITIS--INFECTION

C.G.

65

Rec. papillomata (tr. cell II)

H.B.

63

Papillomata

H.C.

54

Post-op. tr. anaplastic Ca.

G.W.

40

Papillomata

1 yr. 10mths. 0-9 mths. 0-4 mths. 3

yrs. 6 mths.

with 250 kV x-rays; but even with meticulous accuracy, ½ cm. variation in distance of bead to bladder is difficult to avoid. This makes a difference in a dose of 4,000 rads of ± 1,000 rads. My conclusions regarding intra-cavitary treatment generally are that : - (a) The dose to the bladder mucosa should not exceed the dose which would allow complete and rapid healing in skin using the same time factors. (b) For conditions of the bladder mucosa it can be useful. (c) Where there are tumours of mixed sizes, it should only be used if the larger tumours can be dealt with by diathermy or partial excision. (d) The dose and timing of radiation must be carefully chosen relative to the timing of surgical

Necrosis

Died metas.

Ta. wire

Degenerate Ca.

Well 6 yrs.

Au OD Ta.

No Ca.

Died 0-4 mths.

DX+Au

J

AnN 3

I procedures so as to permit healing. CONCLUSIONS

(a)

Megavoltage Beams Radiation.-~ It is be-

coming increasingly clear that external radiation with high energy long F.S.D. beams is the method of choice for tumours too large for implantation. There are not m a n y series available on which to assess results. Mr Wallace has informed me that five-year survival rates in his series with megavoltage are 40 per cent for mucosal tumours, 13 per cent for those invading muscle, and 14 per cent when there is perivesical invasion. These are about twice as good as was obtained with 250 kV radiation. Combined with previous partial cystectomy, the corresponding survivals were 80 per cent mucosa,

BLADDER

NEOPLASMS--THE

CHALLENGE

38 per cent muscle and 26 per cent perivesical. My cases treated by external cobalt radiation so far can never be as good as this. We have been using our cobalt machine since October 1958. Of eight cases of mucosal stage carcinoma, two died of recurrence at three years, two years and two months respectively. Three others alive at present developed recurrences, and only three are well, at one, two and three years respectively. For cases involving muscle, of twenty-two cases completing treatment, twelve are alive, at periods varying from four months to three years; three o f these are known to have recurrences. One feature of external radiation which I did not appreciate before hearing Mr COX of the Westminster Hospital at a British Institute of Radiology meeting, is that tumours may continue to improve for as long as a year after treatment, with the implication that further treatment should be withheld for this period unless there is a definite indication. (b) The late complications o f external radiation, becoming more k n o w n now that so many patients can be treated by high energy beams, are radiation

BLADDER

TO

THE

13

RADIOTHERAPIST

cystitis with severe bleeding in some instances, and contraction of the bladder due to fibrosis. With regard to the first of these, it is difficult to k n o w when it is due to radiation, ordinary cystitis being so c o m m o n . The bleeding, however, has been discussed a good deal, though the cause is still obscure. My cases subjected to total cystectomy are listed in table 12, shown with the reason for the operation. Apart from the fact that out of ten cases referred as cases of papilloma at least six proved to have carcinoma within less than one-and-a-half years of being referred, it seems that in one case only was there bleeding with no turnout found, although one case (H. C.) had a generalised cystitis due to radiation, or radiation plus infection. Bleeding from telangiectases when the epithelium is intact is less serious because it is more easily controlled. It would seem that telangiectasia is likely to be due to fibrosis in the deeper layers of the bladder and deep in the pelvis, and is therefore more likely to develop pari-passu with increase in volume irradiated to high dosage and consequent reduction of escape routes for the blood. If the

TUMOURS

PISTS NO T'MENT

x=o

(0

D

xxooo xx® XX®

EXT. O) O9


(xeoee Roe cx®ooo xo (X00

xo® xo ®

.oo
I ~(o× ~oee@( ~®0. e o :<

lIC)~x×

I


xooo

~8 O

0®~ 0~

(xoo (X®

IMPLAN"

Qxi INTRACAV. RADIATION

o =UROLOGIST

0

x ;RADIOTHERAPY • =SURGEON

DIVERSION OF URINE

® =COMBINED

®0 00

TOTAL CYSTECTOMY

F.B.

G

r'

000

PARTIAL CYSTECTOMY

~-

==,

OPEN DIATHERMY

QI 0¢

I

M.B.

9Q

(o

J}O

= F e w Benign Tumours = M a n y Benign Tumours Muc. =Ca, confined tO M ucosa Mus. = C a , invading muscle P.V. = Perivesica[ extension P.F. =Pelvic Fixation Mets, = W i t h or without metastases

~eo

ID g

C

TRANSURETHRAL RESECTIO

IXOOOe ix~° ~o,

(00

141,

EXTERNAL DIATHERMY

~oo ~

QX

EB.

MB.

Muc.

Mus.

FIT.

PV

P.E L'_mets.

EB.

MB.

Muc.

Mus.

UNFIT.

19 R e s u l t s o f o p i n i o n poll o n m e t h o d s o f treatment. FIG.

P.V

PF + mcts.

14

CLINICAL

bladder epithelium is completely denuded, telangiectases are not visible, and bleeding occurs from the dilated exposed thin-walled capillaries. The loss of the epithelium permits diffusion of urine into the lamina propria and produces an inflammatory reaction for which there would seem to be no remedy except diversion of the urine.

(c)

General radiotherapeutic

considerations.-

The reasons for these catastrophes are not completely understood. It may be that infection during or after treatment is a pre-disposing factor, and this should therefore be effectively dealt with before treatment. It seems likely that overdosage may be largely responsible, The radiotherapist must ensure accuracy at all stages culminating in absorption of rads in the bladder, including not only calibration, suitable isodose data and accurate timing of doses, but also the planning of the treatment, correction for obliquity of fields if necessary, and accurate beam direction. Even then there is the risk, especially if no applicators are used, of a patient moving during treatment. The planning of the treatment should aim at using volumes as small as consistent with including the whole tumour. It seems desirable to concentrate on the local tumour, since the cases with pelvic fixation have virtually no prognosis, and because failure is mostly due to recurrence, infection or radiation sequelae in the bladder. By keeping it full during treatment, part of the bladder could be saved from a high dose. However, the position of the tumour could be known accurately only in those with fixed, i.e., hopeless, tumours, so that the present practice of treating with the bladder empty seems best. An exception might be made in the case of growths sited near the neck of the bladder, since this is relatively fixed. It seems desirable to ensure that the rectum is empty at each session of treatment, so that its contents will not, by displacing the bladder, cause variation in the position of the tumour at different sessions. Ifallthe treatment could be carried out with the patient supine, it would help towards accuracy. Dose and time relations are all-important. Perhaps we stick too slavishly to the first dosage scheme mentioned in print. Small increases in dose, or decrease in time, with careful clinical comparison of patients, might be a useful approach to finding an optimum, assuming that it is likely that the number we first thought of is not the last word. Treatment Policy.--I am grateful to those surgeons and radiotherapists who replied to the questionnaire seeking information about their treatment policies. Replies were received from five urologists, five general surgeons in the Oxford region, three pairs of urologists and radiotherapists, and eight radiothera-

RADIOLOGY

pists. The replies have been summarised in Figure 19, which obviously needs time to study. The popularity of high e n e r g y external radiation for unfit patients and for relatively advanced lesions in fit patients is obvious. Partial cystectomy seems not to be recommended in replies solely from radiotherapists. Total cystectomy is less favoured ' by urological surgeons than by general surgeons. Urologists with radiotherapist and radiotherapists alone are much in favour of implants for carcinoma invading muscle or confined to mucosa. A relatively high number, of general surgeons favour partial cystectomy in these lesions. Diathermy for all forms of mucosal tumours, whether benign or malignant, is preferred by most, with open diathermy in selected cases. No one likes intracavitary treatment. I think that in selected cases of primary small multiple mucosal tumours, intracavitary gold or yttrium is still good treatment provided always that its limitations are realised and the optimum dose is found. Supplementary diathermy, or diathermy alone, must be used for single papilliferous lesions which fail to respond to radiation, and for relatively large residues. For tumours considered to invade muscle, it is reasonable to give pre-operative radiation to 3,000 rads with intra-cavitary cobalt beads, partial cystectomy on the following day, and a tantalum wire implant to the wound at the time. For a turnout at the base of the bladder, partial cystectomy would be contra-indicated in favour of an implant. For tumours with perivesical extension or pelvic fixation, external radiation only would be reasonable, using 6?< 8 to 8 × 10 fields only. Alternatively, total cystectomy might be indicated for extra-vesical extension alone, or with previous external radiation. Contact x-ray treatment after open diathermy, or partial cystectomy, has been used successfully in two of our operable cases, and has been reported by a German author as being successful in eight out of ten cases. The dose with contact x-rays at the inner surface of the muscle, per 1,000 rads given to the surface, can be 900 rads. Total cystectomy even for early (mucosal) tumours was reported by Fletcher Colby from the Massachusetts General Hospital as giving only 16 per cent five-year survivals, as compared with 100 per cent when treated by any conservative methods. For tumours invading muscle, the corresponding figures were 8 per cent and 11 per cent respectively. The implication is that the complications of the total cystectomy kill the patient rather than the cancer. The present use of antibiotics and correction of the electrolyte difficulties may be responsible for the vastly better five-year

BLADDER

NEOPLASMS--THE

C H A L L E N G E TO T H E R A D I O T H E R A P I S T

survivals which have been obtained by Riches (mucosal 39 per cent, muscular 10 per cent, perivesical 4 per cent) and by Wallace (mucosal 50 per

The causes of death in my series are as shown in Table 13. It is clear that most of the deaths are due to persistent neoplasm in the bladder, or to complications resulting f r o m this or other treatment. The

cent). TABLE 13 CAUSES OF DEATH

Condition when first een t

Cause of Death Papilloma

Pelvic I Fixation -t- Metastases

Mucosa only involved

Muscle invaded

Extravesical invasion

13

17

28

33

Total

I

4 (2 Ca.)

Bladder disease

95

(5 Ca.)

Metastases

3

14

3

2

Renal failure

1

4

2

1

!

I

24 10

Cardio-vascular

3

1

3

2

0

Other Ca. (rectum)

2

0

0

0

0

2

Other cause

1

4

1

0

2

8

Unknown

0

0

6

4

0

14

22

45

39

38

Total

I

15

~

I

9

10 158

Causes other t h a n " bladder disease" are only specified when the bladder was clear at the time of death).

Fi~. 20 Reproduction of operation sheet.

16

CLINICAL RADIOLOGY

presence of metastases, or death from other causes has only been specified w h e n the bladder has been clear. There are, of course, m a n y aspects of bladder t u m o u r s besides the ones I have touched u p o n . I have in m i n d the enthralling work of B o y l a n d a n d his co-workers o n the carcinogenic action of orthophenols a n d t r y p t o p h a n metabolites set free by enzyme action i n the bladder. It m a y be that the p H of the urine is i m p o r t a n t in c o n n e c t i o n with such enzyme action. The p H might also be i m p o r t a n t in c o n n e c t i o n with the d e v e l o p m e n t of r a d i a t i o n cystitis. Loss of the t r a n s i t i o n a l cell epithelium, which is n o r m a l l y i m p e r m e a b l e to urinary solutes, m u s t surely influence p r o f o u n d l y the healing of ulcers after r a d i a t i o n or diathermy. I would like to stress the need for accurate records and suitable a r r a n g e m e n t s for follow-up cystoscopy. It seems likely that it m a y soon be possible to s u p p l e m e n t records of this type (Fig. 20) with photographs. It m a y seem necessary to stress the desirability in clinical work for early c o - o p e r a t i o n in each case

between the surgeons, who should be urologists, a n d the radiotherapist before, d u r i n g a n d after treatment. They should see the patients together at all stages. Finally, I should like to t h a n k all my colleagues, physicists, clerical staff a n d a n y others who, in the U n i t e d Oxford Hospitals, Oxford R e g i o n a l Board or elsewhere, have helped me to p r o d u c e this lecture. Especially m y thanks are due to M r Barr a n d Miss H u n t of the Oxford R e g i o n a l Board statistical d e p a r t m e n t , a n d to D r J. M. Brindle, who has helped i n m a n y ways u p to the final stages of p u b l i c a t i o n . , REFERENCES

BOYLAND, E. (1959). In Tumours of the Bladder, p. 83. Ed. WALLACE,D. M. Edinburgh: Livingstone. Cox, R. (1960). Treatment of Carcinoma of the Bladder: a Symposium. Brit. J. RadioL 33, 480. KERR, W. S. & COLBY, F. H. (1951). J. Urol. 65, 841. RICHES, E. W. (•958). Malignant Disease of the Urinary Tract, (Lettsomian Lectures). Trans. med. Soc. Lond. 74, 77. WALLACE,D.M. (1959). Tumoursof the Bladder. Edinburgh: Livingstone.

BOOK REVIEW Radiodermatitis. By ERVIN EPSTEIN. Pp. 178, 36 illus. 1962. Springfield: Thomas. $7.75. " THAT Dr Ervin Epstein would accept the challenge to write about the history, biology, use and abuse (in his own inimitable way) of ionising radiation is in itself an achievement." Thus, Dr Arthur C. Curtis in his foreword to the book, and one's hopes are raised high from the beginning. Unfortunately, they are not sustained for it soon becomes clear that only the surface of the subject can be scratched in 175 pages of text. It is hard not to be put off by the style. One example from the second line of the author's preface in the form of an apologia, may suffice. " Obviously, just because a hypertonic scribophiliac reaches the decision that he desires to write a book on a given subject does not constitute a convincing reason for a hard-headed business man to invest his dollars in the publication of the book . . . " So, asks the author " Why this book?" The question, rhetorically put, is answered by pointing out how greatly the advantages of ionising radiation outweigh the disadvantages. Few nowadays would disagree. The racy and rather breathless style, rich in clich6s, is maintained through chapter 1, " Introduction " and chapter 2 on " History and outlook of radiodermatitis." In chapter 3 on " Etiology" it becomes clear that the author has a high regard for x-ray therapy in the management of acne and other skin conditions. This is, of course, at variance with practice in this country where superficial x-ray therapy is probably used to a diminishing extent and in much smaller doses than those mentioned in this book. Chapter 5 on "Clinical picture " justifies our conservatism. A good collection of clinical photographs and an adequate text sets out the calamities that can follow unwise

irradiation. A satisfactory account on "Histopathology" is given, followed by short chapters on "Diagnosis " and " Prognosis and treatment." Most of this is noncontroversial and the author rightly stresses the difficulty of diagnosis between necrotic ulceration and recurrent carcinoma of the skin and the importance of biopsy. A satisfactory bibliography follows. The second section of the book concerns special aspects of the subject written by five collaborators. A general account of the effects of small doses of radiation by Dr Dell F. Dullum pro-. Lies a satisfactory thumbnail sketch of the subject as do:3 Dr John Spencer Felton's account of " Occupational Exposure." But the sting is in the tail, and the last chapter by Mr Bossio, Dr Rees and Mr Hassard on " X-ray therapy and malpractice" makes one realise how fortunate we are in this country that irradiation is mostly under strict physical control. The poor dermatologists who produced radionecrosis in the treatment of athlete's foot, psoriasis, plantar warts and so on, were certainly made to pay heavily for their sins and, as the author understandably points out in his addendum " The subject of radiodermatitis is one fraught with dangers of litigation and financial catastrophe for the physician." One wonders to what extent the fear of litigation may induce radiotherapists to keep dosage down to figures lower than they would otherwise advise. It is hard to see to whom this book is directed, unless Dr Epstein is writing, in admonition, to his brother dermatologists. Radiotherapists in this country will applaud faintly and feel perhaps rather smugly, that we order it better here. The book is well produced though only a few colour plates in place of some of the thirty-six illustrations would have helped. The index is adequate. P. STmCKLAND.