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The Treatment of carcinoma of the bladder with megavoltage irradiation — A clinical trial
THE
TREATMENT. MEGAVOLTAGE
OF CARCINOMA IRRADIATION
OF -
A
THE BLADDER WITH CLINICAL TRIAL
R. FINNEY, M.B., B.S., F.R.C.S. (E)., F.F.R.
Radiotherapy Department, Newcastle General Hospital IN most eentres the treatment of carcinoma of the bladder by external irradiation is now undertaken with high energy irradiation employing a linear accelerator or tele-cobalt apparatus. The advantages which are well known, namely absence of skin reaction, increased depth dose and simplification and ease of treatment are dependent on the physical characteristics of the beam. Since the introduction of the 4 MeV linear accelerator to this centre in 1953, the number of cases treated by external irradiation has increased markedly and at the same time treatment by interstitial methods has decreased proportionately. Our experience from preliminary pilot studies suggested that too great a daily dose resulted in excessive reactions and the policy in the light of this experience has been to deliver a 'tumour' dose of 200 rads per day to a total dose of 6,500 rads, treatment being given daily, 5 days per week i.e. 6,500 rads in 6-7 weeks for fields of 8 × 8 cms. Survey of the literature shows an appreciable variation in dose-time relationship employed by different centres. Thus Bloom (1963), employing 2 MeV or 6 MeV x-ray therapy has given 6,500 r in 6-7 weeks, whilst at the Christie Hospital the dosage is 5,500 to 6,000 in 3 weeks, with which symptoms due to bladder reaction have not been severe (Pointon, 1960). Ellis (1963), reviewing present dosage schemes from a number of the larger centres showed that the equivalent dosage in 1 month (in rads) varied from 5,100 to 6,875 employing either a linear accelerator or Cobalt Unit. Because of the wide variation in daily dosage in use for bladder cancer, it was decided to undertake a clinical trial to study reactions, tumour regression and case survival with different dose rates.
All the cases in this trial were referred from the Urological Centre in the Newcastle General Hospital, having been fully investigated in that specialist department. The investigations included cystoscopy and bimanual examination under anaesthesia with staging of the tumour, according to the recommendations of the British Institute of Urology (Pugh, 1959) (Fig. 1), biopsy and histological grading, renal function tests and urine culture. Each case was discussed at a weekly combined Urological/Radiotherapy meeting and 109 cases with tumours of high grade malignancy or showing infiltration were accepted for external irradiation. This represents 30 per cent of the total 385 cases seen between 1959 and 1962. In the majority of cases muscle involvement was present (stage 2). The distribution of tumours by stage and histological grade was comparable in each treatment group. In each case a 3 field irradiation plan was used-1 anterior and 2 posterior fields, usually 8 × 8 to 10 × 8 cms. in size (Fig. 2). The patients' symptoms were carefully recorded before treatment, at weekly intervals during irradiation and after treatment and details of any medical treatment recorded. Cystoscopy was carried out at 3, 6 and 12 months from time of cessation of radiotherapy and subsequently at 6 or 12 monthly intervals depending on the tumour response.
REACTIONS Reactions occurring during the course of irradiation can be grouped under two main headings : (1) Bladder Reactions including frequency, dysuria, stress, urgency and passage of clots and debris. (2) RectaI Reactions or proctitis, characterised by PROGRAMME AND MATERIAL diarrhoea, frequency, tenesmus and colic. The trial was planned to investigate 3 different In many cases bladder symptoms were present daily 'tumour dose' rates:--200, 250, and 300 before radiotherapy commenced, i.e. frequency, rads 5 days per week, to an overall dose of 6,500 dysuria, urgency, etc. and in these cases a 'reaction' rads. 'Tumour dose' was the model dose* for was recorded only if symptoms worsened. Table lI the whole bladder volume. The daily dose for relates dose and radiation reactions. each patient was decided by random selection. A more detailed analysis of the severity of the *That dose which is found to occur most frequently in the reaction is made in Table III. The most striking feature is the increasing planned treated area. 324
MEGAVOLTAGE
IRRADIATION--A
frequency and severity of rectal reactions as the daily dose increases; the bladder reactions show no great difference.
, ai2r dose (rads)
rectal changes (Table IV). In only one case could the late changes be described as severe--necessitating a colostomy. TABLE 4 RECTAL REACTIONS
Daily t u m o u r dose (rads)
No or cases ._ _
Grade ~ Well diff.
/ /37
40
Well diff.
65
Anaplastic
35 %
~Well diff.
I
Stage 60~
Anaplastic 36
23 67 0
Stage 1 Stage 2 Stage 3
30~ 70 0
Stage 1 Stage 2 Stage 3
66~
Anaplastic
Stage 1 Stage 2 Stage 3
34
27~ 64~ 9%
TABLE 2
No. of cases
Bladder reactions
36
21
36
27
14
37
23
25
Acute reactions
Chronic reactions
25
5
200 300
TABLE 5 DYSURIA
BLADDER AND RECTAL REACTIONS
Daily tumour dose (rads)
325
TABLE 1
200
300
TRIAL
GRADE AND STAGE OF TUMOUR
36
250
CLINICAL
Daily tumour dose (rads)
Symptom improved
Symptom unchanged
Symptom deteriorated
200
7
14
14
250
4
20
13
300
3
20
12
Rectal reactions
In a few cases improvement of symptoms occurred as the course of treatment proceeded. Only with the relief of dysuria was there any difference between the 3 groups, when the greatest improvement occurred in the group receiving the lowest dose rate (Table V).
TABLE 3 BLADDER AND RECTAL REACTIONS
Daily tumour dose (rads) 200
Bladder Rectal Frequency + --
250
+ --
300
+ --
Dysuria
17
+
19
--
19
+
17
--
18 16
+ I
]
--
11 25
~3 --33
( + +1)
16 20
+14 --22
(++3)
+25
(++7)
15 9
--9
+ Reaction marked + + Extremely severe + Severe. Reaction absent 4- Minimal - - Absent.
Further analysis reveals that the acute rectal reactions usually subside within 3-4 weeks of cessation of irradiation and only in a minority of cases, in the 300 rads/day group, do symptoms persist or recur due to delayed or chronic radiation
INFECTION It has always been assumed that the presence of infection in the treated volume (as demonstrated by bacteriological urine culture) aggravates irradiation reactions. Efforts are therefore made to control any infection by a course of the appropriate antibiotic. Complete eradication of infection is usually impossible, especially in the presence of a large ulcerated neoplasm. Table VI shows the relationship between infection and ensuing degrees of reaction. It would appear that there is no obvious correlation between infection and reaction--a severe reaction resulting in a high proportion of cases irrespectivo of whether the original urine culture was positive or negative. The picture may of course have been modified as a result of the pre-irradiation antibiotics employed in those cases with a positive bacteriology.
326
CLINICAL
t Muscular tumours. Stage T2.
Mucosal tumours, Stage TI.
Perivesical turnouts, Stage T3.
Pelvic fixation, Stage 14.
FIG. 1 Tumour staging, according to the recommendations of the British Institute of Urology (Pugh, 1959).
TABLE 6 1NFECTION-REAC I-ION
Daily tumour dose (rads)
Clinical reactions
Urine bacteriology
200
+ve --ve
19 17
+13 + 7
( + +10) (++6)
250
+ve --ve
14 24
+10 +20
(++9) ( + +15)
300
+ve --ve
20 16
+14 +9
( + +11) (++8)
TABLE 7 CASES ALIVE AND WELL, TUMOUR FREE
Daily tumour dose (rads)
200
250
300
No. at risk (1 yr.) Alive 1 yr,
36 21
36 26
37 22
No. at risk (2 yr.) Alive 2 yr.
30 14
29 11
28 17
No. at risk (3 yr.) Alive 3 yr.
16 12
RADIOLOGY
T U M O U R REGRESSION Tumour regression as judged by post irradiation cystoscopy findings was studied at the different dose rates. The numbers at risk at each cystoscopie check were roughly the same with general diminution in numbers as the time increased from cessation of irradiation. It is too early to give significant 5-year survival rates. It is evident from Table VII that (1) The number of eases showing complete tumour regression are almost the same in all groups up to the one year check time and (2) After one year considerably more patients show tumour regression in the highest dose group. These differences have been analysed statistically. STATISTICAL ANALYSIS The 3-year results were explored statistically using the Chi 2 test. (1) Difference between 200 and 250 rads/day. There is no significant difference between these survival rates. (2) Difference between 200 and 300 rads/day. i.e. 4/16 as compared with 12/16. X2--6'125 P='015 This is a highly significant result. As there is no significant difference between the 200 fads/day and the 250 rads/day groups, a more powerful test can be obtained by combining these two groups and comparing the results of this combination with those of the 300 rads/day. (3) Difference between combined groups (200 and 250) and 300 rads/day. i.e. 9/32 as compared with 12/16. X~--7-78 P-- -005 Again, this is a highly significant result. Statistical Result.--The 3 year survival figures for 300 fads/day patients are better than both the 200 and 250 rads/day groups by highly significant factors. CONCLUSIONS (1) In the majority of cases the bladder reactions--frequency and dysuria--worsen as the treatment proceeds. There is no difference in the incidence of severe reactions between any of the groups surveyed. In a few cases symptoms improve during treatment. (2) The acute rectal reactions--diarrhoea, frequency and tenesmus---increase in incidence and severity as the daily dose increases. In a number of cases treatment had to be interrupted because of the severity of these reactions predominantly in the high dose group. The acute reactions subside within 3-4 weeks post-radiation and only in a
MEGAVOLTAGE
IRRADIATION--A 8s9
i
CLINICAL
327
TRIAL
cm..
\
\ \
!
\
lOa/o///
X ~o*J, \
/
// //
\ I /
/ / /
\
/
\
\
\N N
\ \ \
6O [,',
7i 9crn
719cm.
Fit. 2 Three field irradiation technique used in the treatment of bladder tumours.
minority of cases do delayed or chronic changes produce symptoms. (3) The highest incidence of tumour regression in the three groups investigated occurred at the highest daily dose rate of treatment, i.e. 6,500 rads in 4 weeks. This appears to be more effective than 6,500 rads in 6 weeks. These results are statistically significant. SUMMARY A clinical trial is reported o f the treatment o f carcinoma o f the bladder employing 4 M e V external irradiation. Three different daily dose regimes are investigated from the point o f view o f immediate reactions and subsequent tumour regression. The bladder reactions s h o w e d no differences between the 3 doses employed. The rectal reactions
increase in incidence and severity as the daily dose increases. T u m o u r regression occurred more frequently in the group treated at the highest daily dose. This result was significant statistically. Acknowledgements.--I would like to record my thanks to Mr. J_ Swinney and Mr. W. K. Yeates, from whose Department of Urology all the cases have been referred, to Mr. C. J. Thurgar for continued help and advice and to Mr. J. Haggith for the statistical analysis. My thanks are also due to E. & S. Livingstone Ltd. & Mr. D. M. Wallace for permission to reproduce fig_ 1.
REFERENCES BLOOM, H. J. G. (1963). Personal communication. ELUS, F. (1963). Clin. RadioL, 14, 1. POrNTO•, R. C. S. (1960). Proc. Roy. Soc. Med., 53, 244. PUGH, R. C. B. (1959). ! n Tumours of the B/adder. Ed. D. M. Wallace. Edinburgh: Livingstone, p. 149.
TREATMENT. MEGAVOLTAGE
OF CARCINOMA IRRADIATION
OF -
A
THE BLADDER WITH CLINICAL TRIAL
R. FINNEY, M.B., B.S., F.R.C.S. (E)., F.F.R.
Radiotherapy Department, Newcastle General Hospital IN most eentres the treatment of carcinoma of the bladder by external irradiation is now undertaken with high energy irradiation employing a linear accelerator or tele-cobalt apparatus. The advantages which are well known, namely absence of skin reaction, increased depth dose and simplification and ease of treatment are dependent on the physical characteristics of the beam. Since the introduction of the 4 MeV linear accelerator to this centre in 1953, the number of cases treated by external irradiation has increased markedly and at the same time treatment by interstitial methods has decreased proportionately. Our experience from preliminary pilot studies suggested that too great a daily dose resulted in excessive reactions and the policy in the light of this experience has been to deliver a 'tumour' dose of 200 rads per day to a total dose of 6,500 rads, treatment being given daily, 5 days per week i.e. 6,500 rads in 6-7 weeks for fields of 8 × 8 cms. Survey of the literature shows an appreciable variation in dose-time relationship employed by different centres. Thus Bloom (1963), employing 2 MeV or 6 MeV x-ray therapy has given 6,500 r in 6-7 weeks, whilst at the Christie Hospital the dosage is 5,500 to 6,000 in 3 weeks, with which symptoms due to bladder reaction have not been severe (Pointon, 1960). Ellis (1963), reviewing present dosage schemes from a number of the larger centres showed that the equivalent dosage in 1 month (in rads) varied from 5,100 to 6,875 employing either a linear accelerator or Cobalt Unit. Because of the wide variation in daily dosage in use for bladder cancer, it was decided to undertake a clinical trial to study reactions, tumour regression and case survival with different dose rates.
All the cases in this trial were referred from the Urological Centre in the Newcastle General Hospital, having been fully investigated in that specialist department. The investigations included cystoscopy and bimanual examination under anaesthesia with staging of the tumour, according to the recommendations of the British Institute of Urology (Pugh, 1959) (Fig. 1), biopsy and histological grading, renal function tests and urine culture. Each case was discussed at a weekly combined Urological/Radiotherapy meeting and 109 cases with tumours of high grade malignancy or showing infiltration were accepted for external irradiation. This represents 30 per cent of the total 385 cases seen between 1959 and 1962. In the majority of cases muscle involvement was present (stage 2). The distribution of tumours by stage and histological grade was comparable in each treatment group. In each case a 3 field irradiation plan was used-1 anterior and 2 posterior fields, usually 8 × 8 to 10 × 8 cms. in size (Fig. 2). The patients' symptoms were carefully recorded before treatment, at weekly intervals during irradiation and after treatment and details of any medical treatment recorded. Cystoscopy was carried out at 3, 6 and 12 months from time of cessation of radiotherapy and subsequently at 6 or 12 monthly intervals depending on the tumour response.
REACTIONS Reactions occurring during the course of irradiation can be grouped under two main headings : (1) Bladder Reactions including frequency, dysuria, stress, urgency and passage of clots and debris. (2) RectaI Reactions or proctitis, characterised by PROGRAMME AND MATERIAL diarrhoea, frequency, tenesmus and colic. The trial was planned to investigate 3 different In many cases bladder symptoms were present daily 'tumour dose' rates:--200, 250, and 300 before radiotherapy commenced, i.e. frequency, rads 5 days per week, to an overall dose of 6,500 dysuria, urgency, etc. and in these cases a 'reaction' rads. 'Tumour dose' was the model dose* for was recorded only if symptoms worsened. Table lI the whole bladder volume. The daily dose for relates dose and radiation reactions. each patient was decided by random selection. A more detailed analysis of the severity of the *That dose which is found to occur most frequently in the reaction is made in Table III. The most striking feature is the increasing planned treated area. 324
MEGAVOLTAGE
IRRADIATION--A
frequency and severity of rectal reactions as the daily dose increases; the bladder reactions show no great difference.
, ai2r dose (rads)
rectal changes (Table IV). In only one case could the late changes be described as severe--necessitating a colostomy. TABLE 4 RECTAL REACTIONS
Daily t u m o u r dose (rads)
No or cases ._ _
Grade ~ Well diff.
/ /37
40
Well diff.
65
Anaplastic
35 %
~Well diff.
I
Stage 60~
Anaplastic 36
23 67 0
Stage 1 Stage 2 Stage 3
30~ 70 0
Stage 1 Stage 2 Stage 3
66~
Anaplastic
Stage 1 Stage 2 Stage 3
34
27~ 64~ 9%
TABLE 2
No. of cases
Bladder reactions
36
21
36
27
14
37
23
25
Acute reactions
Chronic reactions
25
5
200 300
TABLE 5 DYSURIA
BLADDER AND RECTAL REACTIONS
Daily tumour dose (rads)
325
TABLE 1
200
300
TRIAL
GRADE AND STAGE OF TUMOUR
36
250
CLINICAL
Daily tumour dose (rads)
Symptom improved
Symptom unchanged
Symptom deteriorated
200
7
14
14
250
4
20
13
300
3
20
12
Rectal reactions
In a few cases improvement of symptoms occurred as the course of treatment proceeded. Only with the relief of dysuria was there any difference between the 3 groups, when the greatest improvement occurred in the group receiving the lowest dose rate (Table V).
TABLE 3 BLADDER AND RECTAL REACTIONS
Daily tumour dose (rads) 200
Bladder Rectal Frequency + --
250
+ --
300
+ --
Dysuria
17
+
19
--
19
+
17
--
18 16
+ I
]
--
11 25
~3 --33
( + +1)
16 20
+14 --22
(++3)
+25
(++7)
15 9
--9
+ Reaction marked + + Extremely severe + Severe. Reaction absent 4- Minimal - - Absent.
Further analysis reveals that the acute rectal reactions usually subside within 3-4 weeks of cessation of irradiation and only in a minority of cases, in the 300 rads/day group, do symptoms persist or recur due to delayed or chronic radiation
INFECTION It has always been assumed that the presence of infection in the treated volume (as demonstrated by bacteriological urine culture) aggravates irradiation reactions. Efforts are therefore made to control any infection by a course of the appropriate antibiotic. Complete eradication of infection is usually impossible, especially in the presence of a large ulcerated neoplasm. Table VI shows the relationship between infection and ensuing degrees of reaction. It would appear that there is no obvious correlation between infection and reaction--a severe reaction resulting in a high proportion of cases irrespectivo of whether the original urine culture was positive or negative. The picture may of course have been modified as a result of the pre-irradiation antibiotics employed in those cases with a positive bacteriology.
326
CLINICAL
t Muscular tumours. Stage T2.
Mucosal tumours, Stage TI.
Perivesical turnouts, Stage T3.
Pelvic fixation, Stage 14.
FIG. 1 Tumour staging, according to the recommendations of the British Institute of Urology (Pugh, 1959).
TABLE 6 1NFECTION-REAC I-ION
Daily tumour dose (rads)
Clinical reactions
Urine bacteriology
200
+ve --ve
19 17
+13 + 7
( + +10) (++6)
250
+ve --ve
14 24
+10 +20
(++9) ( + +15)
300
+ve --ve
20 16
+14 +9
( + +11) (++8)
TABLE 7 CASES ALIVE AND WELL, TUMOUR FREE
Daily tumour dose (rads)
200
250
300
No. at risk (1 yr.) Alive 1 yr,
36 21
36 26
37 22
No. at risk (2 yr.) Alive 2 yr.
30 14
29 11
28 17
No. at risk (3 yr.) Alive 3 yr.
16 12
RADIOLOGY
T U M O U R REGRESSION Tumour regression as judged by post irradiation cystoscopy findings was studied at the different dose rates. The numbers at risk at each cystoscopie check were roughly the same with general diminution in numbers as the time increased from cessation of irradiation. It is too early to give significant 5-year survival rates. It is evident from Table VII that (1) The number of eases showing complete tumour regression are almost the same in all groups up to the one year check time and (2) After one year considerably more patients show tumour regression in the highest dose group. These differences have been analysed statistically. STATISTICAL ANALYSIS The 3-year results were explored statistically using the Chi 2 test. (1) Difference between 200 and 250 rads/day. There is no significant difference between these survival rates. (2) Difference between 200 and 300 rads/day. i.e. 4/16 as compared with 12/16. X2--6'125 P='015 This is a highly significant result. As there is no significant difference between the 200 fads/day and the 250 rads/day groups, a more powerful test can be obtained by combining these two groups and comparing the results of this combination with those of the 300 rads/day. (3) Difference between combined groups (200 and 250) and 300 rads/day. i.e. 9/32 as compared with 12/16. X~--7-78 P-- -005 Again, this is a highly significant result. Statistical Result.--The 3 year survival figures for 300 fads/day patients are better than both the 200 and 250 rads/day groups by highly significant factors. CONCLUSIONS (1) In the majority of cases the bladder reactions--frequency and dysuria--worsen as the treatment proceeds. There is no difference in the incidence of severe reactions between any of the groups surveyed. In a few cases symptoms improve during treatment. (2) The acute rectal reactions--diarrhoea, frequency and tenesmus---increase in incidence and severity as the daily dose increases. In a number of cases treatment had to be interrupted because of the severity of these reactions predominantly in the high dose group. The acute reactions subside within 3-4 weeks post-radiation and only in a
MEGAVOLTAGE
IRRADIATION--A 8s9
i
CLINICAL
327
TRIAL
cm..
\
\ \
!
\
lOa/o///
X ~o*J, \
/
// //
\ I /
/ / /
\
/
\
\
\N N
\ \ \
6O [,',
7i 9crn
719cm.
Fit. 2 Three field irradiation technique used in the treatment of bladder tumours.
minority of cases do delayed or chronic changes produce symptoms. (3) The highest incidence of tumour regression in the three groups investigated occurred at the highest daily dose rate of treatment, i.e. 6,500 rads in 4 weeks. This appears to be more effective than 6,500 rads in 6 weeks. These results are statistically significant. SUMMARY A clinical trial is reported o f the treatment o f carcinoma o f the bladder employing 4 M e V external irradiation. Three different daily dose regimes are investigated from the point o f view o f immediate reactions and subsequent tumour regression. The bladder reactions s h o w e d no differences between the 3 doses employed. The rectal reactions
increase in incidence and severity as the daily dose increases. T u m o u r regression occurred more frequently in the group treated at the highest daily dose. This result was significant statistically. Acknowledgements.--I would like to record my thanks to Mr. J_ Swinney and Mr. W. K. Yeates, from whose Department of Urology all the cases have been referred, to Mr. C. J. Thurgar for continued help and advice and to Mr. J. Haggith for the statistical analysis. My thanks are also due to E. & S. Livingstone Ltd. & Mr. D. M. Wallace for permission to reproduce fig_ 1.
REFERENCES BLOOM, H. J. G. (1963). Personal communication. ELUS, F. (1963). Clin. RadioL, 14, 1. POrNTO•, R. C. S. (1960). Proc. Roy. Soc. Med., 53, 244. PUGH, R. C. B. (1959). ! n Tumours of the B/adder. Ed. D. M. Wallace. Edinburgh: Livingstone, p. 149.