Annals of Oncology!: 343-346, 1991. O 1991 Kluwer Academic Publishers. Printed in the Netherlands.
Original article Primary breast cancer: The effect of primary ovarian irradiation R. Nissen-Meyer The Norwegian Radium Hospital, Oslo, Norway
Summary. Between November 1957 and December 1963, 169 premenopausal and 177 postmenopausal patients were included in a randomized clinical trial. In the experimental group ovarian irradiation was given shortly after mastectomy. In the control group ovarian irradiation was planned for the time of first recurrence. The last published follow-up in 1974 [1] revealed a significant effect on disease-free survival both in premenopausal and postmenopausal patients. The latest results from a follow-up conducted in 1989 demonstrate a significant effect also on crude survival in both age groups. As expected, long-term effects are observed exclusively in the premenopausal cohort. Key words: adjuvant endocrine therapy, breast cancer, ovarian irradiation Introduction The first to report on the performance of bilateral oophorectomy to obtain clinical remissions in advanced breast cancer was Beatson [2], in 1896. However, in 1889 Schinzinger [3] had already proposed oophorectomy as adjunct to the surgical treatment for early cases. He repeated his plea for the early application of this new form of treatment in 1905 [4|, stating that his only intention by such a primary castration was to obtain a slower growth rate of the cancer. One hundred years have elapsed since this discussion, but there is still no general agreement on the relative values of 'prophylactic' (better terms are 'primary' or 'adjuvant') and 'therapeutic' castration. The present paper provides a direct comparison of the post-mastectomy effects on crude survival obtained either by ovarian irradiation to all patients after mastectomy, or by adoption of the policy that ovarian irradiation should be given only when a relapse is diagnosed.
Materials and methods
One hundred sixty-nine premenopausal patients with favourable prognoses (94% node negative), and 177 postmenopausal patients (45% node negative) treated at The Norwegian Radium Hospital, were included in a randomized clinical trial. Patients aged 50 years or older were registered as postmenopausal if more than 3 months had elapsed since their last menstrual periods. Patients below the age of 50 were registered as postmenopausal only if more than 6 months had elapsed. Patient entry: November 1957 - December 1963. Routine primary treatment: radical mastectomy
(Halsted), and irradiation of thoracic fields, axilla and supraclavicular field. Randomization: by telephone to a statistician at The Norwegian Cancer Registry, who had prepared lists of random numbers, separately for the premenopausal and postmenopausal series. Random allocation was to either postoperative ovarian irradiation (estimated dose 1000 rads in the ovaries over a period of 6 days), or to control. In the control cases it was planned to perform ovarian irradiation as soon as a relapse was diagnosed, — but circumstances sometimes did not allow this to be done. In some cases the condition of the patient at diagnosis of metastasis was already so poor that transport was not considered feasible. In other cases the patients were so old that the local doctor did not find castration worthwhile, or he found more recently developed treatment methods to be more appropriate. Such problems, however, will always arise when a treatment is scheduled to be given at a later date. The study is therefore a trial of the principles of 'adjuvant' vs. 'therapeutic' castration. In 1.7% of the cases the patient did not receive the primary treatment to which she was randomized, but statistically all were kept in the group to which they were allocated. Follow-up: yearly control up to August 1974. After that date we had more occasional controls and reports, mainly concerning diagnosis and treatment of relapses. Only 3 new recurrences and 4 new cancers in the second breast occurred after August 1974. These were treated at The Norwegian Radium Hospital, or we received reports from the local hospitals. However, with the assistance of The Norwegian Cancer Registry, all living patients were again traced as of December 31st,
344
1988, and all death certificates with the official diag- Table 1. Patient entry and characteristics. noses were examined. The only exceptions were two Premenopausal, Postmenopausal patients who emigrated to the USA after 7 and 19 low-risk years, at times when both were free of disease. Statistical method: Cutler & Ederer maximum utiliControl vs Adjuvant Control vs Adjuvant zation of the life table method in analyzing survival [5]. ovarian ovarian radiation radiation Details of the distribution of the patients and the patient characteristics are specified in Table 1, and the Number cases in which the intended 'therapeutic' castration was randomized 76 93 87 90 not performed are listed in Tables 3 and 4. Age
mean median range
Results and comments The results are shown graphically in Figs. 1 and 2. For computing disease-free survival, diagnoses of local recurrence, distant metastases, new primary cancer in the opposite breast and death were all counted as events, whichever came first. In the series of premenopausal patients with favourable prognoses adjuvant ovarian irradiation had a significant beneficial effect on both disease-free survival and crude survival. The effect on the disease-free survival seemed to increase with increasing years of follow-up. The effect on overall survival came later than the effect on relapses, was not apparent before about 15 years after mastectomy, but was maintained for at least 30 years. Also in the postmenopausal series with an 'average' prognosis the effect on disease-free survival and overall survival was significant. In this age group, however, it was of much shorter duration, and after 10—15 years "V.
PREMENOPAUSAL, LOW-RISK
100-1
DISEASEFREE
44.2
44.5
60.2
44
45
60
59
32-54
25-54
46-77
47-72
Node negative 87 93.5% 72 94.7% Node positive 6 6.5% 4 5.3% Protocol violation castration no castration
3 3.2%
40 46.0% 40 44.4% 47 54.0% 50 55.6%
1 1.1% 2 2.6%
was eliminated by the large number of deaths from old age, which were not related to breast cancer. In the premenopausal series the total number of deaths was reduced from 49.5 to 35.5% (Table 2), and the number living with no evidence of disease (NED) increased from 46.2 to 63.2%. The number of cases developing a new primary cancer in the second breast as her first event was reduced from 12.9 to 2.6%. In the postmenopausal series the number of new primary cancers in the second breast was small (3.4% and 3.3%) - in the same range as in the castrated group of the premenopausal series. POSTMENOPAUSAL
%
SURVIVAL
58.7
lOOn
'
Original article Primary breast cancer: The effect of primary ovarian irradiation R. Nissen-Meyer The Norwegian Radium Hospital, Oslo, Norway
Summary. Between November 1957 and December 1963, 169 premenopausal and 177 postmenopausal patients were included in a randomized clinical trial. In the experimental group ovarian irradiation was given shortly after mastectomy. In the control group ovarian irradiation was planned for the time of first recurrence. The last published follow-up in 1974 [1] revealed a significant effect on disease-free survival both in premenopausal and postmenopausal patients. The latest results from a follow-up conducted in 1989 demonstrate a significant effect also on crude survival in both age groups. As expected, long-term effects are observed exclusively in the premenopausal cohort. Key words: adjuvant endocrine therapy, breast cancer, ovarian irradiation Introduction The first to report on the performance of bilateral oophorectomy to obtain clinical remissions in advanced breast cancer was Beatson [2], in 1896. However, in 1889 Schinzinger [3] had already proposed oophorectomy as adjunct to the surgical treatment for early cases. He repeated his plea for the early application of this new form of treatment in 1905 [4|, stating that his only intention by such a primary castration was to obtain a slower growth rate of the cancer. One hundred years have elapsed since this discussion, but there is still no general agreement on the relative values of 'prophylactic' (better terms are 'primary' or 'adjuvant') and 'therapeutic' castration. The present paper provides a direct comparison of the post-mastectomy effects on crude survival obtained either by ovarian irradiation to all patients after mastectomy, or by adoption of the policy that ovarian irradiation should be given only when a relapse is diagnosed.
Materials and methods
One hundred sixty-nine premenopausal patients with favourable prognoses (94% node negative), and 177 postmenopausal patients (45% node negative) treated at The Norwegian Radium Hospital, were included in a randomized clinical trial. Patients aged 50 years or older were registered as postmenopausal if more than 3 months had elapsed since their last menstrual periods. Patients below the age of 50 were registered as postmenopausal only if more than 6 months had elapsed. Patient entry: November 1957 - December 1963. Routine primary treatment: radical mastectomy
(Halsted), and irradiation of thoracic fields, axilla and supraclavicular field. Randomization: by telephone to a statistician at The Norwegian Cancer Registry, who had prepared lists of random numbers, separately for the premenopausal and postmenopausal series. Random allocation was to either postoperative ovarian irradiation (estimated dose 1000 rads in the ovaries over a period of 6 days), or to control. In the control cases it was planned to perform ovarian irradiation as soon as a relapse was diagnosed, — but circumstances sometimes did not allow this to be done. In some cases the condition of the patient at diagnosis of metastasis was already so poor that transport was not considered feasible. In other cases the patients were so old that the local doctor did not find castration worthwhile, or he found more recently developed treatment methods to be more appropriate. Such problems, however, will always arise when a treatment is scheduled to be given at a later date. The study is therefore a trial of the principles of 'adjuvant' vs. 'therapeutic' castration. In 1.7% of the cases the patient did not receive the primary treatment to which she was randomized, but statistically all were kept in the group to which they were allocated. Follow-up: yearly control up to August 1974. After that date we had more occasional controls and reports, mainly concerning diagnosis and treatment of relapses. Only 3 new recurrences and 4 new cancers in the second breast occurred after August 1974. These were treated at The Norwegian Radium Hospital, or we received reports from the local hospitals. However, with the assistance of The Norwegian Cancer Registry, all living patients were again traced as of December 31st,
344
1988, and all death certificates with the official diag- Table 1. Patient entry and characteristics. noses were examined. The only exceptions were two Premenopausal, Postmenopausal patients who emigrated to the USA after 7 and 19 low-risk years, at times when both were free of disease. Statistical method: Cutler & Ederer maximum utiliControl vs Adjuvant Control vs Adjuvant zation of the life table method in analyzing survival [5]. ovarian ovarian radiation radiation Details of the distribution of the patients and the patient characteristics are specified in Table 1, and the Number cases in which the intended 'therapeutic' castration was randomized 76 93 87 90 not performed are listed in Tables 3 and 4. Age
mean median range
Results and comments The results are shown graphically in Figs. 1 and 2. For computing disease-free survival, diagnoses of local recurrence, distant metastases, new primary cancer in the opposite breast and death were all counted as events, whichever came first. In the series of premenopausal patients with favourable prognoses adjuvant ovarian irradiation had a significant beneficial effect on both disease-free survival and crude survival. The effect on the disease-free survival seemed to increase with increasing years of follow-up. The effect on overall survival came later than the effect on relapses, was not apparent before about 15 years after mastectomy, but was maintained for at least 30 years. Also in the postmenopausal series with an 'average' prognosis the effect on disease-free survival and overall survival was significant. In this age group, however, it was of much shorter duration, and after 10—15 years "V.
PREMENOPAUSAL, LOW-RISK
100-1
DISEASEFREE
44.2
44.5
60.2
44
45
60
59
32-54
25-54
46-77
47-72
Node negative 87 93.5% 72 94.7% Node positive 6 6.5% 4 5.3% Protocol violation castration no castration
3 3.2%
40 46.0% 40 44.4% 47 54.0% 50 55.6%
1 1.1% 2 2.6%
was eliminated by the large number of deaths from old age, which were not related to breast cancer. In the premenopausal series the total number of deaths was reduced from 49.5 to 35.5% (Table 2), and the number living with no evidence of disease (NED) increased from 46.2 to 63.2%. The number of cases developing a new primary cancer in the second breast as her first event was reduced from 12.9 to 2.6%. In the postmenopausal series the number of new primary cancers in the second breast was small (3.4% and 3.3%) - in the same range as in the castrated group of the premenopausal series. POSTMENOPAUSAL
%
SURVIVAL
58.7
lOOn
'
