The Effects of Preoperative Irradiation

Transcription

1 The Effects of Preoperative Irradiation on Primary Tracheal Anastomosis N. Tsubota, M.D., W. J. Simpson, M.D., A. W. P. Van Nostrand, M.D., and F. G. Pearson, M.D. ABSTRACT Preoperative radiotherapy was used in the management of selected patients with cancer of the lung or trachea who might subsequently require segmental resection of bronchus or trachea and reconstruction by primary anastomosis. This study was designed to determine the effects of varying dosages of preoperative irradiation on anastomotic healing. Two rings were resected from the cervical trachea of 20 dogs following irradiation with varying doses of cesium. There were no important adverse effects on healing of the trachea or adjacent organs in dogs receiving up to 3,500 rads. All dogs receiving a higher dose than this developed some anastomotic stenosis, which was severe in 6 of 8 animals. Similar adverse efects were observed in 2 patients managed by preoperative radiotherapy (4,000 rads in three weeks) and tracheal resection with primary anastomosis. n some patients with primary carcinoma of the lung or trachea, it may be evident prior to operation that dissection lines will be close to the margins of gross tumor and that microscopic tumor may remain following resection. This problem frequently occurs in patients with primary carcinoma of the trachea (adenoid cystic carcinoma, squamous cell carcinoma) since nonresectable structures such as the aortic arch and its branches, and the vena cava, lie immediately adjacent to the mediastinal trachea. Both squamous cell carcinoma and adenoid cystic carcinoma are responsive to current techniques of irradiation [ 1-6, 81. Theoretically, radiation therapy is most likely to ablate tumor on the periphery or margin of a neoplasm, and preoperative irradiation should reduce the incidence of local recurrence 151. This study evaluates the effects of varying doses of preoperative irradiation on healing of the tracheal anastomosis and adjacent tissues of the esophagus and spinal cord. Materials and Methods Mongrel dogs were irradiated by means of a cesium teletherapy unit with a source-to-skin distance of 50 cm, using 8 x 10 cm right and left lateral neck fields From the Division of Thoracic Surgery, Department of Radiotherapy, and Department of Pathology, University of Toronto and Toronto General Hospital, Toronto, Ont., Canada. Supported by Grant no. 288, Ontario Cancer Treatment and Research Foundation, Toronto, Ont., Canada. We thank Dr. N. B. Rewcastle, Dr. J. Smialek, and Mr. K. Eken for the neuropathology studies, Mr. J. Crocker for his assistance with Microfil studies, and Mi-. S. Rae for his meticulous technical assistance. Presented at the Eleventh Annual Meeting of The Society of Thoracic Surgeons, Montreal, Que., Canada, Jan , Address reprint requests to Dr. Pearson, Room 120 University Wing, Toronto General Hospital, Toronto, Ont., Canada M5G 1L THE ANNALS OF THORACIC SURGERY

2 Preoperative Irradiation for Tracheal Anastomosis centered on the cervical trachea and including the adjacent esophagus and anterior aspect of the spinal cord. The field for irradiation extended 4 cm on either side of the tracheal segment to be resected. Both fields were treated daily, and fifteen treatments were given over a period of three weeks. The radiation dose was relatively uniform throughout the entire treatment course. The dogs weighed between 17 and 22 kg. The animals were divided into five groups of 4 each: a control group receiving no radiotherapy and four groups receiving 3,000,3,500,4,000 and 5,000 rads of preoperative irradiation, respectively. Three weeks after completion of radiation therapy, a short segment of cervical trachea consistingof the eighth and ninth cartilages was resected and reconstructed by primary anastomosis using interrupted sutures of 3-0 chromic catgut. There was no tension on this anastomosis. Postoperatively the dogs were examined for clinical evidence of tracheal obstruction, which, when present, was characterized by labored breathing on effort, wheezing respiration, and a characteristic hoarse cough. Bronchoscopy and esophagoscopy were done three and six weeks after operation, and again at six months in long-term experiments. Contrast tracheograms using powdered tantalum [7] were obtained shortly before the animals were killed. The postmortem gross appearance and histology of the irradiated and adjacent tissues were recorded. In 8 dogs the tracheal circulation was examined following injection of Microfil* - an orange colored, radiopaque, high-viscosity dilutant - into the arterial side of the circulation. Between 75 and 100 ml of liquid Microfil was injected into each carotid artery immediately after the animals were killed with 10 ml of Lethol (nembutal and alcohol). Prior to Microfil injection, the carotid vessels were ligated inferiorly at the level of the sternal notch and superiorly close to the base of the skull. Better filling of small arterioles was obtained by injecting 1,500 IU of heparin intravenously three minutes before the animals were killed. In each of the five study groups, 3 animals were killed six weeks after tracheal resection and 1 animal was killed after six months. Aside from changes developing at the tracheal anastomosis, no significant anesthetic or postoperative complications were observed, and all animals completed the study protocol. Following postmortem examination the resected tracheal segments were examined by means of paraffin-embedded blocks sectioned both vertically and horizontally. The sections were stained with hematoxylin and eosin. The trachea and esophagus obtained from each dog was fixed in 10% formalin, and multiple paraffin-embedded blocks were obtained. These blocks included sections through the anastomosis site, through irradiated trachea and esophagus away from the anastomosis site, and from nonirradiated trachea and esophagus both above and below the irradiated area. On examination of histological sections, specific note was made of the presence or absence of mucosal ulceration and edema, granulation tissue, vascular or lymphatic dilatation, infiltration with acute or chronic inflammatory cells, and the presence of increased collagen and fibrous connective tissue. Eight specimens were injected with Microfil and roentgenograms made. *Microfil silicone rubber injection compounds, Canton Biomedical Products, Boulder, Colo. VOL. 20, NO. 2, AUGUST,

3 ~ ~~ TSUBOTA ET AL. EFFECTS OF PREOPERATIVE RADIOTHERAPY ON TRACHEAL HEALING IN 20 DOGS Clinical Stenosis Group Signs None Mild Severe Control ,000 rads ,500 rads ,000 rads ,000 rads They were then subjected to a clearing technique* designed to demonstrate more precisely the vascular changes in the region of the anastomosis. Since Microfil is radiopaque it is readily discernible on standard roentgenograms, and its bright orange color makes it clearly visible to the naked eye and through the dissecting microscope once the specimen has been cleared. Results The gross effects of preoperative radiotherapy on tracheal healing are summarized in the Table. The tracheal anastomosis healed well in the 4 control dogs without evidence of ulceration or granulation tissue at interval bronchoscopy ; it was identified as a thin, linear scar without stenosis in the tantalum bronchogram and upon postmortem examination (Fig. 1). In animals receivingup to 3,500 rads preoperatively, no differences were observed from the control group at interval endoscopy or postmortem examination, except in 1 dog that developed mild, asymptomatic stenosis at the anastomosis. The contrast tracheogram and gross appearance of the anastomosis in a dog receiving 3,500 rads preoperatively and killed six weeks after tracheal resection are illustrated in Figure 2. All animals receiving either 4,000 or 5,000 rads of preoperative radiotherapy developed a stricture at the tracheal anastomosis that produced clinical evidence of tracheal obstruction in 7 of the 8 dogs. In 3 of the 4 dogs receiving 5,000 rads the stenosis was severe (Fig. 3). In the 5 animals (1 from each study group) maintained for six months following tracheal resection, no differences were observed in the bronchoscopic or roentgenographic appearance of the anastomosis from the changes documented at six weeks. None of the animals developed radiation esophagitis as evaluated by esophagoscopy and postmortem studies. It appears that the dog esophagus is less sensitive to radiation therapy than the human esophagus, since a dose of 3,000 rads delivered over three weeks frequently produces radiation esophagitis in man. The cervical spinal cord was removed during postmortem examination, using a posterior approach for the dissection. Sections from multiple levels of the cervical cord were stained and processed in paraffin. Sections were stained with hematoxylin and eosin and Lux01 fast blue and then examined with light microscopy. In 1 specimen a focal lesion of acute arteritis was identified, but it is doubtful *The specimens were dehydrated using increasing concentrations of alcohol and then cleared using cedarwood oil. After examination and photography, the specimens were embedded in paraffin wax and sectioned ip the usual manner. 154 THE ANNALS OF THORACIC SURGERY

4 Preoperative Irradiation fm Tracheal Anastomosis FIG. 1. (A) Contrast tracheogram in a control animal killed six weeks after tracheal anastomosis. There is no significant stenosis. (B) Gross appearance of tracheal anastomosis (arrow) in the same animal. The anastomosis is seen as a line of pale, linear scar without stricture. that this was related to the radiation therapy. In the remaining specimens no abnormality was identified that could not be explained on the basis of manipulative and processing artifacts. Specifically, no differences were seen between the control specimens and the cord segments of irradiated animals. It should be noted, however, that the field for irradiation did not extend to the posterior aspect of the spinal cord, and the cord may not have received the same full dosage levels that were delivered to the trachea and esophagus. FIG. 2. (A) Contrast tracheopam six weeks after tracheal anastomosis in an animal receiuing?,500 rads of preoperative irradiation. There is no signafxant stenosis. (B) Gross appearance.f the anastomosis (arrow) in the same animal. VOL. 20, NO. 2, AUGUST,

5 TSUBOTA ET AL. FIG. 3. (A) Contrast tracheogram six weeks after tracheal anastomosis in animal receiving 5,000 rads of preoperative irradiation. Severe stenosis with clinical signs of airway obstruction is present. (B) Gross appearance of tracheal anastomosis in the same animal. A diaphragm of scar tissue is present at the anastornosix HISTOLOGY OF THE TRACHEA Histological sections from irradiated areas of the trachea and esophagus in dogs receiving 3,000 and 3,500 rads showed a minor degree of edema of the tracheal mucosa associated with a sprinkling of chronic inflammatory cells when compared with sections from control dogs. The anastomosis site in these dogs was a thin, flat scar covered with normal respiratory mucosa and showing no increase in vascularity, chronic inflammation, or fibrosis when compared with the controls (Fig. 4A). Sections taken from dogs receiving 4,000 and 5,000 rads revealed increasing degrees of edema and inflammation. The most striking differences, however, were at the site of anastomosis. Those animals which exhibited clinical signs of tracheal stenosis had developed a buildup of capillary-rich granulation tissue at the anastomosis site that protruded into the tracheal lumen and in some cases remained denuded of epithelium (Figs. 4B, 5). The vascular network adjacent to the anastomosis site remained markedly dilated. Edema, chronic inflammation, and fibrosis were all increased at the anastomosis site. All these observations support the contention that the effects of irradiation on sites of tissue injury (in this study, surgical trauma) are due to an alteration in the vascular response that promotes the development of granulation tissue, delays the healing process, and produces increased amounts of connective tissue when healing occurs. In this dog model the critical dose appeared to be between 3,500 and 4,000 rads. Comment It is apparent from this study that, in dogs, preoperative radiotherapy in doses greater than 3,500 rads given over three weeks impairs healing of a tracheal 156 THE ANNALS OF THORACIC SURGERY

6 Preoperative Irradiation for Tracheal Anastomosis FIG. 4. Photomicrographs of longitudinal sections of the trachea. (A) Anastomosis in a dog that received 3,000 rads of preoperative irradiation. The anastomosis is a thin line of scar with intact epathelial cover and without luminal stenosis. (B) Anastomosis in a dog that received 5,000 rads of preoperative irradiation. There is an excess of vascular granulation tissue and fibroplasia at the anastomosis, some death and destruction of one ofthe tracheal cartilages, and obvious compromise ofthe tracheal lumen which resulted in moderately severe stenosis. (Both H t3 E, X 15; reduced 20% for reproduction.) anastomosis and results in a high incidence of marked stenosis. There is some evidence that anastomotic stenosis in man may result from preoperative irradiation at dosage levels similar to those described in the present experiment. In 1970, 1 of our patients underwent carinal resection for adenoid cystic carcinoma with reconstruction by primary anastomosis between the two bronchial stumps and distal trachea. She received 4,000 rads of radiotherapy during three weeks as a preoperative measure. Surgical treatment was delayed for three months after VOL. 20, NO. 2, AUGUST,

7 TSUBOTA ET AL. FIG. 5. (A) Photograph of opened trachea in a control animal killed six weeks after tracheal anastomosis. The circulation was injected with Microfil. There is no important increase in the number ofsmall vessels at the anastomotic site (arrows).(b) Photograph of opened trachea in an animal that received 4,000 rads of preoperative irradiation and was killed six weeks after tracheal anastomosis. Microfil injection demonstrates a very pronounced increase in the number of small vessels at the margins of ths anastomosis (arrows). completion of radiation therapy because of severe and prolonged esophagitis and tracheobronchitis in the irradiated field. Following resection and reconstruction she developed a clearly demarcated band of necrosis on the tracheal side of the anastomosis. This ultimately healed with a moderate stricture that required repeated dilation to maintain a satisfactory airway. Abbey-Smith has reported troublesome anastomotic strictures following sleeve lobectomy and bronchoplasty 158 THE ANNALS OF THORACIC SURGERY

8 Preoperative Irradiation for Tracheal Anastomosis in patients receiving high doses of preoperative radiotherapy (5,000 rads over four or five weeks).* Since 1970 we have treated 7 patients requiring tracheal or bronchoplastic anastomosis with 3,500 rads of preoperative irradiation delivered during three weeks, followed by resection three weeks after completion of treatment. Three patients had adenoid cystic carcinoma of the trachea requiring segmental resection and reconstruction by primary anastomosis. Three patients had squamous cell carcinoma of the bronchus and required sleeve lobectomy and bronchotracheal anastomosis. One patient with squamous cell carcinoma involving the carina had a carinal resection with right pneumonectomy and reconstruction by anastomosis of the left main bronchus to the distal trachea. In none of these 7 patients were there any significant problems with healing at the anastomosis, and none developed marked stenosis. The theoretical rationale for using preoperative irradiation in such patients has been outlined. Assuming that preoperative radiotherapy may reduce the incidence of local recurrence in selected patients, it is still not known whether 3,000 or 3,500 radsadministered during three weeks is an adequate dose. We have reported limited evidence supporting the effectiveness of such dosage levels in the management of a small number of patients with adenoid cystic carcinoma of the trachea [5]. Adequate evaluation will require a longer period of follow-up and greater numbers of patients treated in this fashion. References 1. Attar, S. A., Hankins, J., Turney, S., Mason, G. R., Ramirez, R., and McLaughlin, J. Tracheal obstruction. Ann Thorac Surg 16:555, Grillo, H. C. Reconstruction of the trachea: Experience in 100 consecutive cases. Thorax 28:667, Hajdu, S. I., and Koss, L. G. Cytology of carcinoma of the trachea. Actu Cytol 3:255, Lewit, P., Karman, S., Terracina, S., and Beemer, A. M. Malignant tumors of the trachea. Chest 60:498, Pearson, F. G., Thompson, D. W., Weissberg, D., Simpson, W. J. K., and Kergin, F. G. Adenoid cystic carcinoma of the trachea. Ann Thoruc Surg 18:16, Richardson, J. D., Grover, F. L., and Trinkle, J. K. Adenoid cystic carcinoma of the trachea: Response to cobalt 60. J Thorac Cardiovasc Surg 66:311, Wood, P. B., Nagy, E., Pearson, F. G., and Rae, S. Measurement of mucociliary clearance from the lower respiratory tract of normal dogs. Can Anaesth SOC J 20: 192, Zenker, H. O., Moore, R. L., Baker, D. C., and Lattes, R. Adenoid cystic carcinoma (cylindroma) of the trachea: Case report with nine-year follow-up. Cancer 23:699,1969. Discussion DR. ROBERT J. JENSIK (Chicago, Ill.): At Rush-Presbyterian-St. Luke s Medical Center over the past ten years, tracheal resection with pneumonectomy and tracheobronchial anastomosis for carcinoma has been carried out in 28 patients: 24 synchronous right pneumonectomies, 1 prior right pneumonectomy, and 3 prior left pneumonectomies. *R. Abbey-Smith, personal communication. VOL. 20, NO. 2, AUGUST,

9 TSUBOTA ET AL. Prior radiotherapy was given to 24 patients with a tumor dose usually limited to 4,000 rads, although in 1 patient as much as 6,000 rads was administered. Of 12 patients surviving less than six months, stenosis developed in 1 following a leak. In 15 patients surviving six months to ten years there were no instances of stenosis. I cannot explain the untoward results in the example cited by Dr. Tsubota. This complication has seldom been seen in our surviving patients, which has allowed us to attempt these procedures after prior radiotherapy without any reluctance. DR. PEARSON: In Dr. Jensik's patients, a dosage of 4,000 rads was administered over a period of four weeks. This isequivalent to slightly less than 3,500 rads administered during a three week period. I believe this explains the discrepancy in their observation concerning the absence of adverse effects of preoperative irradiation in patients undergoing tracheal resection with pneumonectomy. 160 THE ANNALS OF THORACIC SURGERY