Int. J. Cancer: 20, 213-218 (1977)
THE INFLUENCE OF THE ANAESTHETIC ON SURVIVAL RATES OF BREAST CANCER PATIENTS AFTER SURGERY I. A. FRIED Prof. N. N. Petrov Research Institute of Oncology, USSR Ministry of Public Health, Leningrad
The end results of therapy of 1,358 breast cancer patients were studied. Anaesthesia was performed by ether-nitrogen-oxygen (554 cases) o r halothanenitrogen-oxygen (804 cases) mixture with addition of oxygen. The method of Holstead was employed in all cases. A comparison of groups of patients on the basis of such parameters as the anaesthetlc used, age and degree of tumour progression (according t o the T N M classification and results of postoperative histological assays) showed them t o be identical. The study showed that the type of anaesthesia influenced the end results of therapy of cancer patients: the survival rates of patients receiving halothane anaesthesia were much higher than those of the ether-anaesthetized patients. The differences were most pronounced among patients who received pre-operative radiation therapy and post-operative chemotherapy as well as in cases of metastasis spread into regional lymph nodes. The mechanism of the effect of the anaesthetic on the survival rates of cancer patients may be explained on the basis of the data available on the varying influences of anaesthetics on the pituitary-adrenal cortex system and carcinemia development during operation as well as the role of immunity i n tumour cell implantation and growth of metastases.
The effect of anaesthesia on the end results of therapy of tumour patients has hardly been discussed until recently. A very few data are available to indicate that both surgery and anaesthesia do influence tumour growth and metastasis development (Fischer and Fischer, 1959; Agostino and Cliffton, 1964; Timoshechkina, 1967, etc.). However, most of these results have been obtained experimentally, while clinical data are very limited. O n the basis of the assumption that surgery and anaesthesia inevitably influence the end results of therapy of cancer patients, we carried out experimental and clinical studies on the effect of anaesthesia and laparotomy on metastasation in experimental animals and on the survival of breast cancer patients, following surgical operations with induction of anaesthesia by gas mixtures (halothanenitrogen-oxygen or ether-nitrogen-oxygen) with addition of oxygen (Fried and Yaremenko, 1974). It was found that fewer metastases are observed in mice and rats with transplantable tumours, following laparotomy under halothane-induced anaesthesia, than in those anaesthetized by ether. Furthermore, following mastectomy, the 5-year survival rates for halothanenarcotized patients were higher than for those
anaesthetized by ether. Since the approach to the problem and the results were unusual, it was decided to continue the studies in order to investigate the influence of ether and halothane anaesthesia on the end results of therapy of breast cancer patients, using a greater number of clinical cases and placing particular emphasis on the consideration of such parameters as age of patients and tumour progression. MATERIAL AND METHODS
Two thousand case histories and charts on the end results of therapy of breast cancer patients available at the Prof. N. N. Petrov Research Institute of Oncology were examined. This figure included all breast cancer patients operated on at the Institute between 1964 and 1973; of these, 1,358 cases who had had mastectomy (Holstead) alone were selected for our study. Anaesthesia had been performed through a mask by mixtures of gases (halothane-nitrogen-oxygen/804 cases, and ethernitrogen-oxygen/554 cases) with addition of oxygen. Since these two types of anaesthesia differ in the main constituents, they will be hereafter referred to as ether and halothane anaesthesia. The statistical treatment of the data was based on the Methodological Instructions on Registration and Appraisal of End Results of Therapy of Cancer Patients (Shnitnikova and Kaufman, 1961), worked out with due regard to some principles of A. Bradford Hill (1958). Application of these methods makes it possible to ascertain the survival rates of cancer patients for each year within any period after the beginning of therapy. Table I shows that age differences between the patients anaesthetized by ether and halothane are statistically insignificant. The average age of the ether-anaesthetized patients was 52.4f0.4 yrs; that of the halothane-anaesthetized patients was 51.810.4 yrs (p>0.05). Tumour progress is classified on the basis of the TNM system and results of post-operative histological assays. It is clear from Table 11 that the differences in tumour progression between Received: November 17, 1976.
214
FRIED TABLE I
The study of anaesthetic effect on the survival rates of breast cancer patients took into account still another factor: whether therapy was confined to surgery or also included additional treatment.
DISTRIBUTION OF BREAST CANCER PATIENTS ACCORDING TO AGE A N D ANAESTHETIC USED Anaesthetic Ether
Age
RESULTS
Halothane
Number of patients
Percentage
All patients
554
100.0
804
100.0
Breakdown: Under 20 20-30 30-40 40-50 50-60 60-70 70-80 Over 80
3 55 174 177 119 25 1
0.510.3 9.911.3 31.412.0 32.012.0 21.5$1.7 4.510.9 0.2*0.1
1 11 76 268 248 165 32 3
0.1 *0.1 1.4f0.4 9.4* 1.O 33.3It1.7 30.91-1.6 20.5% 1.4 4.010.7 0.4f0.2
(years)
Number of patients
In the first place, the yearly rates of survival were established for all the patients operated on for breast tumours, irrespective of whether therapy had been confined to surgery or the operation had been a component of combined or complex treatment. Table 111 shows that the survival rates of the halothane-anaesthetized patients are significantly higher than those for patients with ether anaesthesia, beginning from the third year after operation. This gap continues to increase until year 6 and shows a slight decrease by year 10, the differences being statistically significant. The decreased differences between the two groups of patients, beginning from year 7, may be accounted for by a hypothesis that, with time, the effects of surgical intervention and, subsequently, chemotherapy and ionizing irradiation are less felt, while other factors inherent in ageing come into play. Table IV demonstrates that, during the whole 10-year period, the survival rates for the patients treated only by surgical operation under halothane anaesthesia were invariably higher than for those
Percentage
cancer patients given different anaesthetics are not considerable. Since no marked differences in age and tumour progression between ether- and halothane-anaesthetized patients were found, the two groups of patients may be considered identical as far as these two major parameters are concerned.
TABLE I1 DISTRIBUTION OF BREAST CANCER PATIENTS ACCORDING TO TUMOUR PROGRESSION A N D ANAESTHETIC USED All patients Tumour progression
Number of patients
%
Halothane
%
Number of patients
%
112 15 5 4 4 1
0.9 17.7 15.1 14.6 2.1 5.8 4.1 6.2 1.1 0.4 0.3 0.3 0.2
91 34 37 6 96 92 73 11 31 25 44 1 4 1 2 1
16.4% 1.57 6.1 f 0 . l 6.7fl.l l.lf0.4 17.3+1.6 16.6*1.6 14.lA1.5 2.0&0.6 5.6f1.0 4.5f0.9 7.9k 1.2 0.23z0.2 0.7f0.4 0.2f0.2 0.410.2 0.2&0.2
157 35 41 7 144 113 121 17 48 30 68 14 1 3 2
19.651.3 4.450.7 5.1 +0.8 0.9 f 0 . 1 17.9A1.3 14.1 1 1 . 2 15.0& 1.3 2.1 +0.5 6.010.8 3.750.6 8.5k1 .O 1.8*0.4 O.l%O.l 0.3f0.2 0.2&0.1
1,355
100.0
554
100.0
801
100.0
248 69 78 13 240 205 199 28 79 55
Total
Ether Number of patients
18.3 5.1 5.8
Three patients are excluded, because the tumour of the mammary gland was removed at another hospital.
P
>0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 0.05 >0.05 >0.05 >0.05
215
ANAESTHESIA AND CANCER PATIENT SURVIVAL TABLE 111 YEARLY SURVIVAL RATES OF BREAST CANCER PATIENTS OPERATED ON UNDER ETHER OR HALOTHANE ANAESTHESIA Anaesthetic Ether Years after operation
1 2 3 4 5 6 7 8 9 10
Patients under observation by the beginning of the year
Halothane Survival rates
%
Patients under observation by the beginning of the year
95.210.9 85.91 1.5 77.511.8 71.7* 1.9 67.7 k2.0 62.5 1 2 . 1 60.212.1 58.4*2.1 56.712.1 56.712.1
554 528 472 402 360 322 249 200 123 80
P
0.6 1.5 2.7 3.5 4.0 5.0 3.7 2.8 3.0 2.5
>0.05
%
94.510.8 88.711.1 83.711.3 79.91 1.4 77.8 11.5 75.3 11.5 69.9k 1.6 65.911.7 65.0 f1.7 63.4rt 1.7
804 760 679 496 381 294 154 94 80 60
given ether anaesthesia. This fact by itself shows that the differences are not accidental. It should also be pointed out that all the patients were operated on by surgeons of the same “school” and no changes had been introduced in the technique of Holstead. The survival rates for the breast cancer patients, who had received chemotherapy (Thio-TEPA), were established for 5 years only, because this treatment had been applied on a sufficiently wide scale only within the last 5 years of the period.
t Survival rates
>0.05
t0.002 tO.OO1 0.05
>0.05 >0.05
-
21 6
FRIED TABLE V YEARLY SURVIVAL RATES OF BREAST CANCER PATIENTS WHO RECEIVED ONLY CHEMOTHERAPY AND WERE OPERATED ON UNDER ETHER OR HALOTHANE ANAESTHESIA Anaesthetic Ether
Years after operation
1 2 3 4 5
Halothane
Patients under observation by the beginning of the year
Survival rates
269 259 233 200 178
96.2*1.2 86.812.1 77.9rt2.5 71.8 1 2 . 7 67.912.8
Patients under observation by the beginning of the year
0 ,o,
TABLE VI RELATIONSHIP OF SURVIVAL RATES AND REGIONAL METASTASIS DEVELOPMENT IN CHEMOTHERAPY-TREATED BREAST CANCER PATIENTS FOR THE FIFTH YEAR AFTER OPERATION UNDER ETHER OR HALOTHANE ANAESTHESIA Tumour progression
T1-4NaMo T1-4NtMo
T1-,N2Mo T,.,NIMo
P
0.5 1.5 2.4 2.9 3.1
>0.05 >0.05
%
390 378 342 262 214
ferences in the survival rates were more pronounced in the chemotherapy-treated patients than in those whose treatment was confined to surgery. Table VI demonstrates that in the absence of metastases into regional lymph nodes (T,,NoMo), whatever the size of tumour, no differences in the survival rates, depending on the anaesthetic used, were observed 5 years after operation, while the survival rates for the patients operated on during halothane anaesthesia were much higher than for those receiving ether if patients, who had received a post-operative course of chemotherapy, had metastases into regional lymph nodes. It is clear from Table VTI that, 1 or 2 years after operation, the survival rates for the breast cancer patients who were treated with irradiation before operation and received chemotherapy post-operatively, show no reliable differences with respect to the anaesthetic used, except that these rates were somewhat higher for the ether-anaesthetized patients during the first year after operation. From the third
t
Survival rates
96.9h0.9 90.7 f 1.5 85.2rt1.8 81.712.0 78.6 h2.1
THE INFLUENCE OF THE ANAESTHETIC ON SURVIVAL RATES OF BREAST CANCER PATIENTS AFTER SURGERY I. A. FRIED Prof. N. N. Petrov Research Institute of Oncology, USSR Ministry of Public Health, Leningrad
The end results of therapy of 1,358 breast cancer patients were studied. Anaesthesia was performed by ether-nitrogen-oxygen (554 cases) o r halothanenitrogen-oxygen (804 cases) mixture with addition of oxygen. The method of Holstead was employed in all cases. A comparison of groups of patients on the basis of such parameters as the anaesthetlc used, age and degree of tumour progression (according t o the T N M classification and results of postoperative histological assays) showed them t o be identical. The study showed that the type of anaesthesia influenced the end results of therapy of cancer patients: the survival rates of patients receiving halothane anaesthesia were much higher than those of the ether-anaesthetized patients. The differences were most pronounced among patients who received pre-operative radiation therapy and post-operative chemotherapy as well as in cases of metastasis spread into regional lymph nodes. The mechanism of the effect of the anaesthetic on the survival rates of cancer patients may be explained on the basis of the data available on the varying influences of anaesthetics on the pituitary-adrenal cortex system and carcinemia development during operation as well as the role of immunity i n tumour cell implantation and growth of metastases.
The effect of anaesthesia on the end results of therapy of tumour patients has hardly been discussed until recently. A very few data are available to indicate that both surgery and anaesthesia do influence tumour growth and metastasis development (Fischer and Fischer, 1959; Agostino and Cliffton, 1964; Timoshechkina, 1967, etc.). However, most of these results have been obtained experimentally, while clinical data are very limited. O n the basis of the assumption that surgery and anaesthesia inevitably influence the end results of therapy of cancer patients, we carried out experimental and clinical studies on the effect of anaesthesia and laparotomy on metastasation in experimental animals and on the survival of breast cancer patients, following surgical operations with induction of anaesthesia by gas mixtures (halothanenitrogen-oxygen or ether-nitrogen-oxygen) with addition of oxygen (Fried and Yaremenko, 1974). It was found that fewer metastases are observed in mice and rats with transplantable tumours, following laparotomy under halothane-induced anaesthesia, than in those anaesthetized by ether. Furthermore, following mastectomy, the 5-year survival rates for halothanenarcotized patients were higher than for those
anaesthetized by ether. Since the approach to the problem and the results were unusual, it was decided to continue the studies in order to investigate the influence of ether and halothane anaesthesia on the end results of therapy of breast cancer patients, using a greater number of clinical cases and placing particular emphasis on the consideration of such parameters as age of patients and tumour progression. MATERIAL AND METHODS
Two thousand case histories and charts on the end results of therapy of breast cancer patients available at the Prof. N. N. Petrov Research Institute of Oncology were examined. This figure included all breast cancer patients operated on at the Institute between 1964 and 1973; of these, 1,358 cases who had had mastectomy (Holstead) alone were selected for our study. Anaesthesia had been performed through a mask by mixtures of gases (halothane-nitrogen-oxygen/804 cases, and ethernitrogen-oxygen/554 cases) with addition of oxygen. Since these two types of anaesthesia differ in the main constituents, they will be hereafter referred to as ether and halothane anaesthesia. The statistical treatment of the data was based on the Methodological Instructions on Registration and Appraisal of End Results of Therapy of Cancer Patients (Shnitnikova and Kaufman, 1961), worked out with due regard to some principles of A. Bradford Hill (1958). Application of these methods makes it possible to ascertain the survival rates of cancer patients for each year within any period after the beginning of therapy. Table I shows that age differences between the patients anaesthetized by ether and halothane are statistically insignificant. The average age of the ether-anaesthetized patients was 52.4f0.4 yrs; that of the halothane-anaesthetized patients was 51.810.4 yrs (p>0.05). Tumour progress is classified on the basis of the TNM system and results of post-operative histological assays. It is clear from Table 11 that the differences in tumour progression between Received: November 17, 1976.
214
FRIED TABLE I
The study of anaesthetic effect on the survival rates of breast cancer patients took into account still another factor: whether therapy was confined to surgery or also included additional treatment.
DISTRIBUTION OF BREAST CANCER PATIENTS ACCORDING TO AGE A N D ANAESTHETIC USED Anaesthetic Ether
Age
RESULTS
Halothane
Number of patients
Percentage
All patients
554
100.0
804
100.0
Breakdown: Under 20 20-30 30-40 40-50 50-60 60-70 70-80 Over 80
3 55 174 177 119 25 1
0.510.3 9.911.3 31.412.0 32.012.0 21.5$1.7 4.510.9 0.2*0.1
1 11 76 268 248 165 32 3
0.1 *0.1 1.4f0.4 9.4* 1.O 33.3It1.7 30.91-1.6 20.5% 1.4 4.010.7 0.4f0.2
(years)
Number of patients
In the first place, the yearly rates of survival were established for all the patients operated on for breast tumours, irrespective of whether therapy had been confined to surgery or the operation had been a component of combined or complex treatment. Table 111 shows that the survival rates of the halothane-anaesthetized patients are significantly higher than those for patients with ether anaesthesia, beginning from the third year after operation. This gap continues to increase until year 6 and shows a slight decrease by year 10, the differences being statistically significant. The decreased differences between the two groups of patients, beginning from year 7, may be accounted for by a hypothesis that, with time, the effects of surgical intervention and, subsequently, chemotherapy and ionizing irradiation are less felt, while other factors inherent in ageing come into play. Table IV demonstrates that, during the whole 10-year period, the survival rates for the patients treated only by surgical operation under halothane anaesthesia were invariably higher than for those
Percentage
cancer patients given different anaesthetics are not considerable. Since no marked differences in age and tumour progression between ether- and halothane-anaesthetized patients were found, the two groups of patients may be considered identical as far as these two major parameters are concerned.
TABLE I1 DISTRIBUTION OF BREAST CANCER PATIENTS ACCORDING TO TUMOUR PROGRESSION A N D ANAESTHETIC USED All patients Tumour progression
Number of patients
%
Halothane
%
Number of patients
%
112 15 5 4 4 1
0.9 17.7 15.1 14.6 2.1 5.8 4.1 6.2 1.1 0.4 0.3 0.3 0.2
91 34 37 6 96 92 73 11 31 25 44 1 4 1 2 1
16.4% 1.57 6.1 f 0 . l 6.7fl.l l.lf0.4 17.3+1.6 16.6*1.6 14.lA1.5 2.0&0.6 5.6f1.0 4.5f0.9 7.9k 1.2 0.23z0.2 0.7f0.4 0.2f0.2 0.410.2 0.2&0.2
157 35 41 7 144 113 121 17 48 30 68 14 1 3 2
19.651.3 4.450.7 5.1 +0.8 0.9 f 0 . 1 17.9A1.3 14.1 1 1 . 2 15.0& 1.3 2.1 +0.5 6.010.8 3.750.6 8.5k1 .O 1.8*0.4 O.l%O.l 0.3f0.2 0.2&0.1
1,355
100.0
554
100.0
801
100.0
248 69 78 13 240 205 199 28 79 55
Total
Ether Number of patients
18.3 5.1 5.8
Three patients are excluded, because the tumour of the mammary gland was removed at another hospital.
P
>0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 0.05 >0.05 >0.05 >0.05
215
ANAESTHESIA AND CANCER PATIENT SURVIVAL TABLE 111 YEARLY SURVIVAL RATES OF BREAST CANCER PATIENTS OPERATED ON UNDER ETHER OR HALOTHANE ANAESTHESIA Anaesthetic Ether Years after operation
1 2 3 4 5 6 7 8 9 10
Patients under observation by the beginning of the year
Halothane Survival rates
%
Patients under observation by the beginning of the year
95.210.9 85.91 1.5 77.511.8 71.7* 1.9 67.7 k2.0 62.5 1 2 . 1 60.212.1 58.4*2.1 56.712.1 56.712.1
554 528 472 402 360 322 249 200 123 80
P
0.6 1.5 2.7 3.5 4.0 5.0 3.7 2.8 3.0 2.5
>0.05
%
94.510.8 88.711.1 83.711.3 79.91 1.4 77.8 11.5 75.3 11.5 69.9k 1.6 65.911.7 65.0 f1.7 63.4rt 1.7
804 760 679 496 381 294 154 94 80 60
given ether anaesthesia. This fact by itself shows that the differences are not accidental. It should also be pointed out that all the patients were operated on by surgeons of the same “school” and no changes had been introduced in the technique of Holstead. The survival rates for the breast cancer patients, who had received chemotherapy (Thio-TEPA), were established for 5 years only, because this treatment had been applied on a sufficiently wide scale only within the last 5 years of the period.
t Survival rates
>0.05
t0.002 tO.OO1 0.05
>0.05 >0.05
-
21 6
FRIED TABLE V YEARLY SURVIVAL RATES OF BREAST CANCER PATIENTS WHO RECEIVED ONLY CHEMOTHERAPY AND WERE OPERATED ON UNDER ETHER OR HALOTHANE ANAESTHESIA Anaesthetic Ether
Years after operation
1 2 3 4 5
Halothane
Patients under observation by the beginning of the year
Survival rates
269 259 233 200 178
96.2*1.2 86.812.1 77.9rt2.5 71.8 1 2 . 7 67.912.8
Patients under observation by the beginning of the year
0 ,o,
TABLE VI RELATIONSHIP OF SURVIVAL RATES AND REGIONAL METASTASIS DEVELOPMENT IN CHEMOTHERAPY-TREATED BREAST CANCER PATIENTS FOR THE FIFTH YEAR AFTER OPERATION UNDER ETHER OR HALOTHANE ANAESTHESIA Tumour progression
T1-4NaMo T1-4NtMo
T1-,N2Mo T,.,NIMo
P
0.5 1.5 2.4 2.9 3.1
>0.05 >0.05
%
390 378 342 262 214
ferences in the survival rates were more pronounced in the chemotherapy-treated patients than in those whose treatment was confined to surgery. Table VI demonstrates that in the absence of metastases into regional lymph nodes (T,,NoMo), whatever the size of tumour, no differences in the survival rates, depending on the anaesthetic used, were observed 5 years after operation, while the survival rates for the patients operated on during halothane anaesthesia were much higher than for those receiving ether if patients, who had received a post-operative course of chemotherapy, had metastases into regional lymph nodes. It is clear from Table VTI that, 1 or 2 years after operation, the survival rates for the breast cancer patients who were treated with irradiation before operation and received chemotherapy post-operatively, show no reliable differences with respect to the anaesthetic used, except that these rates were somewhat higher for the ether-anaesthetized patients during the first year after operation. From the third
t
Survival rates
96.9h0.9 90.7 f 1.5 85.2rt1.8 81.712.0 78.6 h2.1
