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Clinical trials in malignant disease
CLINICAL
TRIALS
IN
MALIGNANT
DISEASE
Part VII--Cancer of the Cervix Uteri Evaluation of adjuvant x-ray therapy in Stages 1 and 2--Interim Report RALSTON PATERSON, C.B.E., M.C., M.D., F.R.C.S., F.F.R. and M A R I O N H. RUSSELL, A.I.S., F.S.S.
Christie Hospital, Manchester THIS is the second report bearing on the treatment of cervix cancer. A contrast is made between cases treated by radium alone and cases to which supplementary parametrial x-radiationwas also given. The study has by no means fully matured yet. The provisional findings are, however, of sufficient interest to justify an interim report on that portion of the sample which has now reached or very nearly reached a three-year interval since admission to the study. A detailed five-year report will be given in a few years' time. The statistical principles followed the pattern set out in Part I of this series of reports (Paterson 1958).
material is given in Figure 1 which shows the distribution by age of the two groups, remembering that each case had been allocated to one or other side of the trial in an entirely random manner. SO
'•40 u .~3'0
MATERIAL The trial was started in January 1957 and discontinued in December 1961 by which time a total of 703 cases had been registered into it. The distribution year by year was as follows : - -
2O
87
I
o 20
75
74
69
69
1960
69
54
1961
63
Total
363
I
(22:) cases)
ir
I 30
I 40
I SO.
I 80
I 70
All patients admitted to the trial had to conform to thecriteria :--Aged under seventy; not previously treated in any way; international Stage 1 or Stage 2; no obvious contra-indication to x-ray therapy, e.g, excessive girth. For reasons which will be noted shortly it was considered undesirable to carry out a similar trial for Stage 3 cases. In consequence, a few cases technically international Stage 2, but in which the disease very nearly reached the pelvic walls (borderline Stage 3 cases), were also excluded from the sample with a view to their having x-ray therapy of choice. With that exception, few cases of new cervix cancer (Stages I and 2) were excluded from the trial. The initial justification for planning the trial in this form stems right back to a contrast presented in the " S e c o n d Statistical Report from the Holt Radium Institute" (Paterson, Tod and Russell
64 340
This report analyses the whole of the 1957, 1958 and the first six months of the 1959 material at three years, with life table calculation forward to three-year survival rates of the cases registered to July 1959 in order to build up as large a block of cases as was possible. The total numbers reported on are therefore : Assigned to " With x - r a y " 231 " W i t h o u t x-ray .... 222 Some indication of the true random nature of the B(16)
with'X'ay • I~o X-ray
79
1958
/
(231cascS)
Age Groups Fig.1. Age distribution in decennor~] groups
Without x-ray
1959
J
-~'~
g" Io
I"
1957
/ "" '*'
Lld--
Number of cases I
~//
"
/
Year With x-ray
/~/e//
/ /
17
18
CLINICAL
1946) which is reproduced in full below. As will be noted, it shows apparent trends suggesting that radium alone is superior for Stages 1 or 2, but that the addition of x-ray therapy clearly bettered Stage 3 cases. A further analysis not previously published which lends some support to this timidity in relation to Stage 3 cases is as follows :-(a) In 1943-4-5, owing to war conditions, treatment policy even for Stage 3 cases excluded x-ray therapy. (b) In 1946-7-8-9 normal policy provided supplementary x-ray therapy to Stage 3 cases. The following Table contrasts the five-year survival rate for Stage 3 cases in these two eras. " No x-ray" policy (295 cases)
" With x-ray " policy (490 cases)
Year
Survival rate per cent
Year
Survivalrate per cent
1943 1944 1945
31 31.4 36.3
1946 1947 1948 1949
43.3 36.3 37.2 44.3
Total
33
Total
40.1
TREATMENT TECHNIQUES Treatment technique over the period of the trial conformed to the pattern detailed by Tod and Meredith (1953)--the " Manchester technique." The x-ray therapy, however, was given either by kilovoltage or megavoltage radiation so that there are, in fact, two sub-groups in the " with x-ray t h e r a p y " sample. Standard dosage aimed at over this period was : No x-ray therapy--8,000 r radium dose at point A. With x-ray therapy--kilovoltage, 2,500 rads x-ray point B+7,000 r radium at point A; or, megavoltage, 3,000 rads x-ray point B+7,500 r radium at point A. RESULTS The overall results for the whole interim sample are given in Table 1. TABLE 1 OVERALL RESULTS AT THE THIRD YEAR
Treatment as assigned With x-ray Without x-ray
Number treated
Survival rate per cent
231 222
68.3 67.4
RADIOLOGY
Detailed analysis of the two groups, however, showed an unexpected, and presumptively fortuitous, disparity in the distribution by stages in each of the groups. A more informative finding is therefore that set out in Table 2 showing the results by individual stages (international staging). TABLE 2 RESULTS BY CLINICALSTAGE Stage 1 Treatment as assigned
Stage 2
~ I Survival Nu~nber I Survival N urn°el/ rate treate_~d pe~a~eent treatea per cent
With x-ray
86
Without x-ray .
58
85.6 /
87"2
164
60'4
The year by year results are given in Table 3. TABLE 3 YEAR BY "~EAR RESULTS
Survival rate per cent Treatment as assigned
Number treated 1 yr
2 yr
3 yr
With x-ray
2;T-
87'9
74.5
68 "3
Without x-ray .
222
90"1
74"8
67.4
Division of the cases into two groups by age is given in Table 4. TABLE 4 RESULTS BY AGE
Under 50 years Treatment as assigned
50 years and over
NumberISurvivallNumberlSurvival t r e a t e d pera~ent t r e a t e d pera~;nt
With x-ray
115
69.7
Without x-ray .
110
70.7
116 112
67.1 64.2
The fact that some of the cases had kilovoltage and others megavoltage x-radiation permitted the further sub-analysis shown in Table 5. Excluded from this Table are two cases which, although assigned to x-ray therapy, did not have it because of intercurrent complications. Analyses in any other forms were not informative.
CLINICAL TRIALS IN MALIGNANT DISEASE
19
CANCER OF UTERINE CERVIX
(1932 to September 1939 inclusive--771 cases) CONTRASTOF COMPLETETREATMENTSWITHAND WITHOETX-rtAV Stage 1
Stage 3
Stage 2
Stage 4
Number treated
5-year net survival per cent
Number treated
5-year net survival per cent
Number treated
5-year net survival per cent
Number treated
5-year net survival per cent
Complete with x-ray
23
62
244
44
212
29
55
20
Complete no x-ray .
35
76
117
49
58
25
27
8
Technique
J Stages 3 and 4 summated
Stages 1 and 2 summated Number treated
5-year net survival per cent
Number treated
5-year net survival per cent
Complete with x-ray
267
46
267
27
Complete no x-ray .
152
56
85
20
TABLE 5 RESULTS BY TYPE OF X-RAY
Treatment as assigned
No x-ray
Number treated 58
Stages 1 and 2
Stage 2
Stage 1
Survival Number rate / treated per cent /
Survival Number treated rate per cent
Survival rate per cent
87.2
164
60-4
222
67"4
54.5
107
70"4
58.1
122
67"8
Kilovoltage
38
91.4
69
Megavoltage
48
80.9
74
COMMENTARY We would be prepared to accept these figures-until and if the full analysis shows otherwise or other evidence becomes a v a i l a b l e - - a s indicating that the addition of x-ray therapy in this f o r m to treatment policy for Stage 1 and 2 cervix cancer does n o t improve the prognosis. The c o m p a r i s o n s of kilovoltage with megavoltage radiation does n o t reveal any significant differences. As x-ray therapy entails both time a n d trouble for the patient, and is never without some m i n o r morbidity, it should be regarded in either form as unnecessary i n these early stages. It should be added that a survey of the whole material at one year after t r e a t m e n t does n o t suggest that the later analyses will, in fact, reverse the findings. It has always been p r e s u m e d that the a d j u v a n t x-ray therapy, in addition to extending the fully irradiated volume for the p r i m a r y growth, also
makes a c o n t r i b u t i o n t h r o u g h control of the nearer l y m p h n o d e s - - e s p e c i a l l y the o b t u r a t o r node receiving dosage from b o t h r a d i u m a n d x-ray. O n the other h a n d it greatly enlarges the volume o f tissue carried to full dosage. I f our findings be accepted, the only p r e s u m p t i o n can be that the loss of a few cases because o f involved nodes which might have been controlled is more t h a n compensated for in these earlier cases by the gain from restriction o f irradiated v o l u m e - - a factor which we believe to have greater i m p o r t a n c e t h a n is often realised. REFERENCES PATERSON,RALSTON(19581. J. Fac. Radiol. (Lond.), 9, 80. PATERSON, R., TOD, M., & RUSSELL, M. (1946). Results of Radium and X-ray Therapy in Malignant Disease. Edinburgh: Livingstone. TOD, M. C., & MEREDITH,W. J. (1953). Brit. J. Radiol. 26, 252.
TRIALS
IN
MALIGNANT
DISEASE
Part VII--Cancer of the Cervix Uteri Evaluation of adjuvant x-ray therapy in Stages 1 and 2--Interim Report RALSTON PATERSON, C.B.E., M.C., M.D., F.R.C.S., F.F.R. and M A R I O N H. RUSSELL, A.I.S., F.S.S.
Christie Hospital, Manchester THIS is the second report bearing on the treatment of cervix cancer. A contrast is made between cases treated by radium alone and cases to which supplementary parametrial x-radiationwas also given. The study has by no means fully matured yet. The provisional findings are, however, of sufficient interest to justify an interim report on that portion of the sample which has now reached or very nearly reached a three-year interval since admission to the study. A detailed five-year report will be given in a few years' time. The statistical principles followed the pattern set out in Part I of this series of reports (Paterson 1958).
material is given in Figure 1 which shows the distribution by age of the two groups, remembering that each case had been allocated to one or other side of the trial in an entirely random manner. SO
'•40 u .~3'0
MATERIAL The trial was started in January 1957 and discontinued in December 1961 by which time a total of 703 cases had been registered into it. The distribution year by year was as follows : - -
2O
87
I
o 20
75
74
69
69
1960
69
54
1961
63
Total
363
I
(22:) cases)
ir
I 30
I 40
I SO.
I 80
I 70
All patients admitted to the trial had to conform to thecriteria :--Aged under seventy; not previously treated in any way; international Stage 1 or Stage 2; no obvious contra-indication to x-ray therapy, e.g, excessive girth. For reasons which will be noted shortly it was considered undesirable to carry out a similar trial for Stage 3 cases. In consequence, a few cases technically international Stage 2, but in which the disease very nearly reached the pelvic walls (borderline Stage 3 cases), were also excluded from the sample with a view to their having x-ray therapy of choice. With that exception, few cases of new cervix cancer (Stages I and 2) were excluded from the trial. The initial justification for planning the trial in this form stems right back to a contrast presented in the " S e c o n d Statistical Report from the Holt Radium Institute" (Paterson, Tod and Russell
64 340
This report analyses the whole of the 1957, 1958 and the first six months of the 1959 material at three years, with life table calculation forward to three-year survival rates of the cases registered to July 1959 in order to build up as large a block of cases as was possible. The total numbers reported on are therefore : Assigned to " With x - r a y " 231 " W i t h o u t x-ray .... 222 Some indication of the true random nature of the B(16)
with'X'ay • I~o X-ray
79
1958
/
(231cascS)
Age Groups Fig.1. Age distribution in decennor~] groups
Without x-ray
1959
J
-~'~
g" Io
I"
1957
/ "" '*'
Lld--
Number of cases I
~//
"
/
Year With x-ray
/~/e//
/ /
17
18
CLINICAL
1946) which is reproduced in full below. As will be noted, it shows apparent trends suggesting that radium alone is superior for Stages 1 or 2, but that the addition of x-ray therapy clearly bettered Stage 3 cases. A further analysis not previously published which lends some support to this timidity in relation to Stage 3 cases is as follows :-(a) In 1943-4-5, owing to war conditions, treatment policy even for Stage 3 cases excluded x-ray therapy. (b) In 1946-7-8-9 normal policy provided supplementary x-ray therapy to Stage 3 cases. The following Table contrasts the five-year survival rate for Stage 3 cases in these two eras. " No x-ray" policy (295 cases)
" With x-ray " policy (490 cases)
Year
Survival rate per cent
Year
Survivalrate per cent
1943 1944 1945
31 31.4 36.3
1946 1947 1948 1949
43.3 36.3 37.2 44.3
Total
33
Total
40.1
TREATMENT TECHNIQUES Treatment technique over the period of the trial conformed to the pattern detailed by Tod and Meredith (1953)--the " Manchester technique." The x-ray therapy, however, was given either by kilovoltage or megavoltage radiation so that there are, in fact, two sub-groups in the " with x-ray t h e r a p y " sample. Standard dosage aimed at over this period was : No x-ray therapy--8,000 r radium dose at point A. With x-ray therapy--kilovoltage, 2,500 rads x-ray point B+7,000 r radium at point A; or, megavoltage, 3,000 rads x-ray point B+7,500 r radium at point A. RESULTS The overall results for the whole interim sample are given in Table 1. TABLE 1 OVERALL RESULTS AT THE THIRD YEAR
Treatment as assigned With x-ray Without x-ray
Number treated
Survival rate per cent
231 222
68.3 67.4
RADIOLOGY
Detailed analysis of the two groups, however, showed an unexpected, and presumptively fortuitous, disparity in the distribution by stages in each of the groups. A more informative finding is therefore that set out in Table 2 showing the results by individual stages (international staging). TABLE 2 RESULTS BY CLINICALSTAGE Stage 1 Treatment as assigned
Stage 2
~ I Survival Nu~nber I Survival N urn°el/ rate treate_~d pe~a~eent treatea per cent
With x-ray
86
Without x-ray .
58
85.6 /
87"2
164
60'4
The year by year results are given in Table 3. TABLE 3 YEAR BY "~EAR RESULTS
Survival rate per cent Treatment as assigned
Number treated 1 yr
2 yr
3 yr
With x-ray
2;T-
87'9
74.5
68 "3
Without x-ray .
222
90"1
74"8
67.4
Division of the cases into two groups by age is given in Table 4. TABLE 4 RESULTS BY AGE
Under 50 years Treatment as assigned
50 years and over
NumberISurvivallNumberlSurvival t r e a t e d pera~ent t r e a t e d pera~;nt
With x-ray
115
69.7
Without x-ray .
110
70.7
116 112
67.1 64.2
The fact that some of the cases had kilovoltage and others megavoltage x-radiation permitted the further sub-analysis shown in Table 5. Excluded from this Table are two cases which, although assigned to x-ray therapy, did not have it because of intercurrent complications. Analyses in any other forms were not informative.
CLINICAL TRIALS IN MALIGNANT DISEASE
19
CANCER OF UTERINE CERVIX
(1932 to September 1939 inclusive--771 cases) CONTRASTOF COMPLETETREATMENTSWITHAND WITHOETX-rtAV Stage 1
Stage 3
Stage 2
Stage 4
Number treated
5-year net survival per cent
Number treated
5-year net survival per cent
Number treated
5-year net survival per cent
Number treated
5-year net survival per cent
Complete with x-ray
23
62
244
44
212
29
55
20
Complete no x-ray .
35
76
117
49
58
25
27
8
Technique
J Stages 3 and 4 summated
Stages 1 and 2 summated Number treated
5-year net survival per cent
Number treated
5-year net survival per cent
Complete with x-ray
267
46
267
27
Complete no x-ray .
152
56
85
20
TABLE 5 RESULTS BY TYPE OF X-RAY
Treatment as assigned
No x-ray
Number treated 58
Stages 1 and 2
Stage 2
Stage 1
Survival Number rate / treated per cent /
Survival Number treated rate per cent
Survival rate per cent
87.2
164
60-4
222
67"4
54.5
107
70"4
58.1
122
67"8
Kilovoltage
38
91.4
69
Megavoltage
48
80.9
74
COMMENTARY We would be prepared to accept these figures-until and if the full analysis shows otherwise or other evidence becomes a v a i l a b l e - - a s indicating that the addition of x-ray therapy in this f o r m to treatment policy for Stage 1 and 2 cervix cancer does n o t improve the prognosis. The c o m p a r i s o n s of kilovoltage with megavoltage radiation does n o t reveal any significant differences. As x-ray therapy entails both time a n d trouble for the patient, and is never without some m i n o r morbidity, it should be regarded in either form as unnecessary i n these early stages. It should be added that a survey of the whole material at one year after t r e a t m e n t does n o t suggest that the later analyses will, in fact, reverse the findings. It has always been p r e s u m e d that the a d j u v a n t x-ray therapy, in addition to extending the fully irradiated volume for the p r i m a r y growth, also
makes a c o n t r i b u t i o n t h r o u g h control of the nearer l y m p h n o d e s - - e s p e c i a l l y the o b t u r a t o r node receiving dosage from b o t h r a d i u m a n d x-ray. O n the other h a n d it greatly enlarges the volume o f tissue carried to full dosage. I f our findings be accepted, the only p r e s u m p t i o n can be that the loss of a few cases because o f involved nodes which might have been controlled is more t h a n compensated for in these earlier cases by the gain from restriction o f irradiated v o l u m e - - a factor which we believe to have greater i m p o r t a n c e t h a n is often realised. REFERENCES PATERSON,RALSTON(19581. J. Fac. Radiol. (Lond.), 9, 80. PATERSON, R., TOD, M., & RUSSELL, M. (1946). Results of Radium and X-ray Therapy in Malignant Disease. Edinburgh: Livingstone. TOD, M. C., & MEREDITH,W. J. (1953). Brit. J. Radiol. 26, 252.