ENHANCING EFFECT OF THORACOTOMY ON TUMOR GROWTH IN RATS*1

Transcription

1 ENHANCING EFFECT OF THORACOTOMY ON TUMOR GROWTH IN RATS*1 Takao HATTORI, Yuichiro HAMAI, Hiroshi IKEDA, Tatsuzi HARADA, and Toshiyuki IKEDA Department of Surgery, Research Institute for Nuclear Medicine and Biology, Hiroshima University*2 To indicate the influence of operative stress on tumor growth, thoracotomy and/or laparotomy were performed 48hr after intraperitoneal or intravenous inoculation of Sato lung cancer into Donryu rats. Survival period, number of metastatic nodules on the surface of the lungs, and the percentage-area of metastases in the frontal section through pulmonary hilus were examined. By thoracotomy and laparothoracotomy the survival period of the tumor-inoculated rats was reduced significantly compared with that of the control but difference between these two test groups was not significant. Also there was no significant difference between the laparotomy group and the control. The results obtained in the number and percentage-area of metastatic nodules were quite similar to that observed in the survival period. Correlation between the number and the percentage-area of metastatic nodules was highly significant. The meaning of the stress of thoracotomy in cancer treatment is discussed. It is generally accepted that surgery is the most powerful means for the cure of cancer, as shown in the history of surgery for gastric cancer in Japan. By escalation of operative intervention to extirpate all the lymph nodes with the stomach and sometimes a part of neighboring tissues, the long-term survival rate of patients with gastric cancer has increased strikingly. In the case of gastric cancer located near the esophagocardial junction, however, the situation differs from it. Resection of esophagocardial cancer can now be carried out with a reasonably low mortality via thoraco-abdominal approach but the prognosis of patients so treated does not seem to have changed over the last two decades. The difficulty of detecting esophagocardial cancer in the early stage was the only excuse for its poor prognosis. Hitherto the influence of surgical stress of thoracotomy on tumor growth has not come up for discussion. Now the operative procedure for esophagocardial cancer via thoraco-abdominal approach does not seem to justify enforcement of the expense and discomfort to the patients in view of the poor prognosis so far obtained. On the other hand, new surgical techniques for esophagocardial cancer, which was established by us via transabdominal approach obviating thoracotomy, gave good clinical results.6) These clinical experiences have stimulated us to design an experiment to test our hypothesis that operative stress of thoracotomy might, at times, enhance the tumor growth in the host. MATERIALS AND METHODS

2 T. HATTORI, ET AL. the metastases to the whole area of the section. The values of the above three determinations in the test groups were expressed as T/C, the percentage to the control values. RESULTS Effect of Respirator on Tumor Growth To clarify the effect of artificial respiration using intratracheal intubation and a rodent respirator on the tumor growth, laparotomy was performed under artificial respiration in one group and under spontaneous respiration in the other on day 2 after inoculation. As shown in Table I, the survival period after intraperitoneal or intravenous inoculation and the number of metastatic nodules on the lungs after intravenous inoculation indicated no difference between the two groups. Survival Period The results are shown in Tables II and III. In both experiments of intraperitoneal and intravenous inoculation, the survival period was significantly reduced by the stress of thoracotomy and laparothoracotomy compared with the control, but no significant difference was observed between these two test groups. Difference was also not seen between the laparotomy group and the control. The differences were clearer in the case of a smaller size of inoculum. Number of Metastatic Nodules The result is given in Table IV. In the group of 105 cell inoculation, laparotomy did not enhance the number of metastatic nodules on the lungs Gann

3 THORACOTOMY AND TUMOR GROWTH Table II. Survival Period of Donryu Rats Inoculated with SLC Intraperitoneally in Relation to Operative Stress Figures in parentheses show the number of rats surviving over 50 days. Each experimental group consisted of 10 rats. Table III. Survival Period of Donryu Rats Inoculated with SLC Intravenously in Relation to Operative Stress Table IV. Number of Metastatic Nodules on the Lungs of Donryu Rats Inoculated with SLC Intravenously in Relation to Operative Stress

4 T. HATTORI, ET AL. Table V. Percentage-area of Metastatic Nodules in the Lungs of Donryu Rats Inoculated with SLC Intravenously in Relation to Operative Stress but thoracotomy and laparothoracotomy did. In the group of 104 cell inoculation, increase in the number of metastatic nodules was demonstrated in all of the three test groups, but significant difference from the control was obtained only in the thoracotomy and laparothoracotomy groups. In the group of 103 cell inoculation, increase in the number was seen in the thoracotomy and laparothoracotomy groups but the difference was not significant, probably due to large deviation in each case. Percentage-area of Metastatic Nodules As shown in Table V, the results obtained were quite similar to those of the number of metastatic nodules. Thoracotomy and laparothoracotomy increased the percentage-area of metastatic nodules significantly compared with the control and the difference was clearer when the size of inoculum was smaller. As shown in Fig. 1, the percentage-area was directly proportional to the number of metastatic nodules with a high coefficient of correlation. DISCUSSION We have suspected that the surgical stress of thoracotomy or laparothoracotomy might depress general resistance of the patient. However, the direct evidence that thoracotomy or laparothoracotomy enhances the growth of the tumor has not been obtained yet. Surgeons aim at low mortality from operation even in the treatment of cancer and their con- Fig. 1. Coefficient of correlation and regression line of the percentage-area against the number of metastatic nodules on the lungs of Donryu rats inoculated with 104 SLC cells intravenously cern does not seem to be directed to enhancing the effect of operative stress itself on the growth of the tumor. With improvement in cytological techniques, an increased number of investigators have found cancer cells in the venous blood draining the tumor and in the peripheral blood of patients with various malignant neoplasms. Even after curative surgery tumor cells are found in the blood. On the other hand that the passage of tumor cells through the blood does not necessarily cause metastases has been frequently suggested since Goldman4) first stated this view in Gann

5 THORACOTOMY AND TUMOR GROWTH Nevertheless, no conclusive evidence has been presented as to why the circulating tumor cells might form secondary foci in some instances and not in others. Many experimental factors have been known to increase the number of metastases in vivo. They are massage,8,10,14) local X-ray irradiation,9,11) total body irradiation,11) elevated environmental temperature,13) Trypan Blue inoculation into the host,3) pregnancy,5) and surgical stress. Although there has been speculation as to the possibility that surgical trauma results in a more rapid growth of tumor, little factual evidence is available. Shatten,15) and Lewis and Cole12) reported increased incidence of pulmonary metastases following total removal of the primary tumor or amputation of the limb with tumor. Buinauskas et al.1) reported an increase in the "take" of Walker-256 cells by the stress of celiotomy performed just before subcutaneous inoculation of the cells into rats. Fisher and Fisher2) investigated the influence of surgical stress on the incidence of hepatic metastases after cell inoculation into the portal vein. The increased incidence was observed when inoculation was immediately followed by partial hepatectomy. Partial hepatectomy had a less effect when performed 24hr after inoculation and no greater incidence of metastases was found in the operated group than in the control, when hepatectomy was performed 48hr later. They emphasized a transient period after operation as an important factor for the stress of hepatectomy influencing the rapid growth of tumor cells. Thus, a few reports on the enhancing effect of abdominal surgery on tumor growth could be seen but none has been on the enhancing effect of thoracotomy, probably due to the difficulty in performing thoracotomy safely in small animals. In this study, the reduction of survival period and increased incidence in the number and percentage-area of metastatic nodules of the lungs were clearly shown by the stress of thoracotomy and laparothoracotomy after intraperitoneal or intravenous inoculation of tumor cells. On the other hand, laparotomy alone was indicated to give no significant enhancing effect on tumor growth. Thoracotomy was made in the right thorax and metastatic nodules were examined on both lungs. As the lungs of the rats consist of four lobes in the right and one lobe in the left, the difference the number of metastatic nodules between the two sides could not be evaluated, but there was seen no difference in the percentage-area of metastatic nodules among the five lobes of the lungs. From these findings it is presumed that the enhancing mechanism of tumor growth by thoracotomy depends on general resistance of the host rather than on local factors. At the first glance, these data might appear to be a point against thoracotomy in cancer treatment but, on the contrary, if these results are applicable to clinics, we might improve our surgical results by neutralizing the deleterious effect of thoracotomy on the host resistance. One attempt is our by-pass procedure for esophagocardial cancer, which consists of transabdominal removal of the esophagocardial lesion and re-establishment of alimentary continuity at the cervical esophagus, thus obviating thoracotomy.6) As described in our previous paper,7) this experimental system of Donryu rats and SLC tumor cells seems to be a very useful tool to examine surgical stress quantitatively, on which little is yet known. Further studies on this line is in progress. in (Received December 26, 1977) REFERENCES

6 T. HATTORI, ET AL. Gann