Journal of Surgical Oncology 11:261-267 (1979)

Survival Rates of Breast Carcinoma Patients After Surgery and Anaesthetic .......................................................................................... .......................................................................................... ELIAS ALSABTI,MD,PhD Eighty-nine breast cancer patients were studied for the end results of therapy. During surgery, the anaesthesia administered was either halothane (61 cases) or ether (28 cases) mixture with nitrogen and oxygen. The holstead method for mastectomy was used for all cases. The results showed that the type of anaesthesia influenced the end results of therapy of breast cancer patients. The survival rates of patients receiving halothane were much higher than those of ether anaesthetized cases. The differences were most pronounced among cases who received both preoperative radiotherapy and postoperative chemotherapy, and in cases with metastasis into regional lymph node. A comparison of groups of patients on the basis of such parameters as the anaesthetic used, age and degree of tumor progression (according t o TNM classification and postoperative histological assays) showed them t o be well matched. These results may be explained by the effects of the anaesthesia on the role of immunity in controlling tumor cell implantation and growth of metastasis.

.......................................................................................... .......................................................................................... Key words: breast cancer, halothane, ether, holstead mastectomy

INTRODUCTION The effect of anaesthesia on the end results of therapy of tumor cases has only recently been discussed; a group of investigators [Fried and Yaremenko, 19741 carried out experimental and clinical studies on the effects of anaesthesia and laparotomy on metastases in experimental animals, and on survival of breast cancer patients, following surgical operations with induction of anaesthesia by gas mixtures (halothane-nitrogenoxygen or ether-nitrogen-oxygen) with addition of oxygen. Some data are available to indicate that both surgery and anaesthesia do influence tumor growth and metastasis From the Royal Scientific Society, Amman, Jordan. Address reprint requests to Dr. Elias Alsabti, MD, c/o MIS. W. Aljaff, Flat No. 5, 8 Norfolk Terrace, Brighton BNI 3AD, England.

0022-4790/79/1103-0261$01.70 @ 1979 Alan

R. Liss, Inc.

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development [Fischer 1959; Agostino, 19643. However, most of these results were obtained in experimental systems while clinical data are very limited. Fried and Yaremenko found that fewer metastases are observed in mice and rats with transplantable tumors, following laparotomy under halothane-induced anaesthesia than in those anaesthetized by ether. They also found five-year survival rates for halothanenarcotized cases were higher than for those anaesthetized by ether. Since the approach to the problem was unusual, we decided to carry out studies to investigate the influence of ether and halothane anaesthesia on the end results of therapy in breast carcinoma, studying all clinical cases in our hospital with emphasis on matching age of patients and tumor progression.

MATERIALS AND METHODS One-hundred and fifty case histories from the Main Hospital, Amman, Jordan were reviewed. This number included all breast cancer patients operated on at that hospital between 1970 and 1977; of these, 89 cases who had holstead mastectomy alone, were selected for this study. Anaesthesia was administered through a mask by mixture of halothane-nitrogen-oxygen for 61 cases, and ether mixture for 28 cases with addition of oxygen. Since these two types of anaesthesia differ in their main constituents, they will be hereafter referred to as ether and halothane anaesthesia. Age difference between the patients anaesthetized by ether and halothane are statistically insignificant as seen in Table I. The average age of the ether-anaesthetized patients was 43 ? 0.8 years; that of the halothane-anaesthetized patients was 42 t 0.6 years. The TNM system for the classification of tumor progress was used as well as results of postoperative histological assays. It is demonstrated in Table 11 that the differences in tumor progression between patients given different anaesthetics were not considerable. Since no marked differences in age and tumor 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. This study took into account another important factor; whether therapy was confined to surgery alone or also included additional treatment.

RESULTS Table I11 shows that the survival rates of all halotkane-anaesthetized patients in the study were higher than those for patients with ether anaesthesia, beginning from the third year after operation. This gap continues t o increase until year 4 and shows a slight decrease TABLE 1. Distribution of Breast Cancer Patients According to Age and Anaesthetic Used Anaesthetic Age (years) under 20 20- 29 30-39 40-49 50-59 60+

Total

Ether No. of cases 0 0

Halothane % 0 0

4 12 8 4 __

14.3 42.9 28.5 14.3

28

100%

No. of cases 0 1 11

28 14 7 61

% 0 1.6

17.9 45.1 22.8 12.0 100%

Total 0 1 15 40 22 11 --

89

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TABLE 11. Distribution of Breast Cancer Patients According to Tumor Progression and the Anaesthetic Used Anaesthetic

TABLE 111. Years of Survival of Patient With Breast Cancer Operated on Under Ether or Halothane Anaesthesia Ether anaesthesia

Years after surgery

No. cases

Halothane anesthesia

Survival rate %

No. cases

Survival rate %

61 56 49 41 31 21 12 7

92.5 f 1 .O 87.4 f 0.9 84.2 f 1.1 76.9 f 1.3 68.8 f 1.4 58.6 k 1.6 56.8 k 1.8 55.9 ? 2.1

~~

28 26 22 17 10 6 3 2

93.4 f 0.8 84.9 f 1.2 78.5 1.3 61.4 2 1.3 59.7 f 1.5 51.4f1.6 50.1 f 1.8 49.8 2 2.0

*

by year 7, the difference being consistently noticeable. That differences started to decrease from the sixth year, may be accounted for by a hypothesis that, with time, the effects of surgery, chemotherapy and the radiotherapy are less evident, while other “factors” inherent in aging are more important. When these surgical patients are further evaluated so that only those receiving additional therapy including chemotherapy, hormone therapy or radiotherapy a larger difference is noted between the two groups. Table IV shows that, during the whole seven-year period, the survival rates for the patients treated only by surgical operation under halothane anaesthesia were invariably higher than for those with ether. These data show that the differences are not accidental.

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TABLE IV. Years of Survival of Patients With Breast Cancer Untreated With Hormones or Radiotherapy or Chemotherapy and Surgery and Surgery was Done Under Ether or Halothane Ether anaesthesia Years after surgery

No. cases

Survival rate 9%

19 18 15 12 9 6 4 2

34.7 f 0.6 85.8 f 0.7 81.5 f 0.8 71.2 f 1.0 70.9 f 1.1 66.3 f 1.3 65.4 f 1.3 61.9 k 1.5

Halothane anaesthesia No. cases 32 31 29 27 23 19 15 11

Survival rate % 98.1 f o . 8 94.2 f 1.0 91.7 f 1.1 85.7 f 1.2 82.4 f 1.4 19.5 f 1.5 75.0 f 1.5 61.4 f 1.5

No changes were introduced in the holstead technique. Survival rates for the breast cancer patients who received chemotherapy (Thio-TEPA) were established for five years, because this treatment was applied on a sufficiently wide scale only within the last five years of the study period. Table V shows that, beginning with the second year after surgery, the survival rates for the breast cancer patients who were operated on under halothane with subsequent chemotherapy, were higher than for those anaesthetized with ether. This difference continued to increase and reached maximum after four years. A comparison of the data presented in Tables IV and V shows that the differences in the survival rates were more pronounced in the chemotherapy-treated patients than in those whose treatment was confined to surgery. It can be seen in Table VI that in the absence of metastases into the regional lymph nodes (T14 NoMo) regardless of the size of tumor, no difference in the survival rates for patients receiving both types of anaesthetic, were observed four years after operation. However, survival rates of halothane-anaesthetized cases were much higher than etheranaesthetized patients who had received postoperative chemotherapy, but had metastases into regional lymph nodes. Table VII shows that, one year after surgery, the survival rates for the breast cancer cases who were treated pre-operatively with radiotherapy and postoperatively with chemotherapy, were essentially alike for both methods of anaesthesia. Survival rates were higher for the ether anaesthetized patients during the first year, while from the second year on, the survival rates of women receiving halothane anaesthesia were higher than those for ether. The survival rates of the halothane group, for the fifth year after surgery, were close to those of the first year in the ether group, that is an indication that halothane is an important factor in the improvement in the end results of treatment of breast cancer patients.

DISCUSSION The data in this paper shows that survival rates for breast cancer patients operated on under halothane anaesthesia are higher for each year of the postoperative follow-up than for the ether, An explanation of the mechanism of anaesthetic effect on the survival rates of cancer patients may be offered on the basis of available data on the condition of the pituitary-

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TABLE V. Years of Survival in Patients Receiving Only Chemotherapy After Mastectomy under Ether or Halothane Anaesthesia Anaesthetic Ether Years after surgery

No. cases

Halothane

No. cases

Survival rate %

Survival %

~

15 14 11 8

1 2 3 4

96.9 f 0.4 89.1 f 0.6 80.6 f 0.9 76.3 f 1.1

25 24 21

97.8 f 0.7 81 .O f 0.9 70.2 k 1.2 66.5 k 1.4

17

TABLE VI. Survival of Chemotherapy-Treated Breast Cancer Patients for the Fourth Year After Surgery Under Ether or Halothane and Its Relationship to Regional Metastasis Survival rates Tumor progression

Ether

Halothane

TI-4NOMO T1-4NIMO

89.7 f 1.2

91.2 f 0.8

51.4 f 2.3

84.9 Zk 1.2

T1-4NZMO

44.2 2 3.1

62.3 f 1.8

T1-4N3MO

11.8 k 3.6

51.7 f 2.2

TABLE VIII. Survival of Breast Cancer Patients Receiving Reoperative Irradiation and Postoperative Chemotherapy and Were Operated on Using Ether or Halothane as Anaesthesia Survival rates Years after operation 1 2 3 4

Ether 92.3 f 1.4 72.7 k 2.6 51.8 f 3.9 43.5 f 4.8

Halo t hane 86.2 f 0.6 84.5 f 0.9 79.2 k 2.1 74.0 k 2.7

adrenal cortex during surgery and anaesthesia, or o n the carcinemia development during operation. The most interesting explanation is one concerning the role of immunity in controlling implantation of tumor cells and metastases development. As surgery has tremendous impact on organs of the body, causing changes in their function, stress causes changes in pituitary-adrenal cortex pathways and the release of great amounts of glucocorticoids into the blood. Numerous authors have shown that tumor cells circulate in the blood stream of cancer patients and this is one of the causes of development of distant metastases after the removal of malignant tumor [Cardozo, 1970; Salsbury, 19751. The hypothesis that there is a correlation between the frequency of distant metastases and the quantity of blood borne tumor cells (whose existence was only supposed before adequate techniques for determining the tumor cell content in blood) has not proved fully valid. This is mostly attributed t o differences in the immunologic responses of the patients.

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Many articles have been published that raised blood-glucocorticoid levels promote carcinogenesis [Dilman, 19741 . The increased incidence of tumor metastases [Crile 1965; Cole et al, 1961; Boyerid et al, 19671 seems to be due t o the activation of the pituitary adrenal cortex system and hypercorticoidism during operations. Surgically induced suppression of immunologic reactivity promotes tumor cell circulation in the blood and metastatic implantation. Ether acts as a stimulant of the sympatico-adrenal systems, and sometimes its effect is so strong that a model of “ether-induced stress” has been developed in experimental endocrinology. Ether blocks the pituitary-adrenal cortex systems less completely than halothane in protecting the organism [Oyama et al, 1968; Clarke et al, 19701 from raised cortisol levels and subsequent decreased immunoresponsiveness. The experiments done by Fried, revealed that the blood-cortisol was raised in laparotomized tumor-bearing animals and this rise was greater with ether than halothane mixture. Also, a direct correlation between blood-cortisol level and the number and weight of metastases was observed, ie, plasma cortisol level was higher and there were more metastases in ether anaesthetized animals, while the blood corticosterone level was lower and there were fewer metastases in the halothane anaesthesia group [Fried and Yarmenko, 19731, As is well known, death of breast cancer patients is mostly due to growth of distant metastases. Therefore, it may be supposed that halothane during surgery will permit less release of glucocorticoids than during ether anaesthesia. Thus, immunologic reactivity is suppressed t o a lower degree making tumor cell implantation less favorable. Humphrey et al [ 19701, however, noticed that halothane anaesthesia doesn’t cause any noteceable changes in the immunological condition of humans, possibly clouding the above hypothesis. Regarding this study, we suggest that further studies on patients with tumors elsewhere in the body may yield similar data, concerning the effect of anaesthesia on end results of therapy. Therefore, the role of anaesthesia in the survival rates of cancer patients must be investigated thoroughly.

ACKNOWLEDGMENTS Many thanks to His Royal Highness, Crown Prince Hassan of Jordan, for his support and encouragement. Thanks to Prof. D. Manania, Dr. A. Hiari, Dr. N. Maita and Dr. M. Milli for their help in getting the case histories. Thanks t o Dr. H. Tadie (Dept. Microbiology) for his help in translating the Russian articles.

REFERENCES Agostino D, ClifftonE: Anesthetic effect o n pulmonary metastasis in rats. Arch Surg 88:735-738, 1964. Boyerid B, Rudenstam C: Effect of heparin, plasminogen and trauma o n tumor metastases. Acta Pathol Microbiol Scand 69: 28- 34, 1967. Cardozo PL: Tumorzell befunden im peripheren blut. Med Klin 65:2095-2096, 1970. Clarke RSI, Jonston H,Sheridan B: The influence o f anaesthesia and surgery o n plasma cortisol, insulin and FFA. Brit J Anaesthesia 42:295-299, 1970. Crile C: The danger of surgical dissemination of papillary carcinoma of thyroid. Surg Gynecol Obstet 102:161-165, 1956. Cole W,McDonald C, Roberts S , Southwick H: “Dissemination of Cancer,’’ New York, 1961. Dilman VM: Endocrinological oncology. Medizina (Russian translated by Dr. H.Tagie), 1974.

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Fischer B, Fischer E: Experimental studies in factors influencing hepatic metastases. Ann Surg 50~731-734,1959. Fried IA, Yaremenko KV: The influence of anaesthesia on metastases development following operation. Vopr Onkol 20:43-47, 1974 (Translated from Russian). Humphrey LY, Amerson YR, Frederichson EL: Preliminary observations on the effect of halothane and oxygen on immunologic response in man. Anaesthesia Analg Curr Res 49:809-815, 1970. Oyama T, Saito T, Isomatsu T, Samejuno N, Hemura T, Arimura A: ACTH and cortisol level in man during diethyl ether anaesthesia. Anaesthesiology 29:559-564 (1968). Oyama T, Shibata S, Matsumoto F, Takiguchi M, Kudo T: Effect of halothane on adrenocorticol function in man. Can Anaesthesiology Soc J 15:258-266 (1968). Salsbury AY: The significance of circulating cancer cell. Cancer Treatment Rev 2:55-72 (1975). Yaremenko KV, Fried IA: The functional activity of the pit-adrenal system and development of metastases of experimental tumors. Vopk Onkol 19:77-80 (1973) (Translated from Russian).

Survival rates of breast carcinoma patients after surgery and anaesthetic.

Journal of Surgical Oncology 11:261-267 (1979) Survival Rates of Breast Carcinoma Patients After Surgery and Anaesthetic ...
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