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Effect of preoperative irradiation on healing of low colorectal anastomoses
Effect of Preoperative Irradiation on Healing of Low Colorectal Anastomoses
Leon Morgenstern,MD, FACS, Los Angeles, California George Sanders, MD, Los Angeles, California Erlk Wahlstrom,MD, Los Angeles, California Joseph Yadegar, MD, Los Angeles, California Pamela Amodeo, MA, Los Angeles, California
The role of preoperative irradiation followed by operative resection in the treatment of rectal carcinoma is a subject of current evaluation and controversy [l-3]. Proponents of routine preoperative irradiation for low lying rectal carcinoma claim to have shown that such treatment enhances survival statistics and should be used adjunctively before operation when cure is the objective [4,5]. Surgeons, however, fear the
adverse effects of such pretreatment, the most important of which is the effect on anastomotic healing. Not only is the lower rectum a formidable area from the technical points of access and maneuverability, but its tendency toward poor anastomotic healing is equally notorious [6,7]. In early clinical studies of routine preoperative irradiation, no increase in operative morbidity or mortality was reported [3]. The operations performed, however, were primarily abdominoperineal resections. In several recent studies [2,8], a high incidence of anastomotic leakage has been reported when a low anterior resection was performed after preoperative irradiation. To study the effect of preoperative irradiation on the healing of low colorectal anastomoses in a controlled fashion, we administered high-dose rectosigmoid irradiation to dogs. The dosage schedule was patterned after that used in clinical practice by Stevens et al [2] and Kligerman et al [3]. All anastomoses were studied at the time of death.
course of external beam irradiation to the lower midabdomen and pelvis. The irradiation was delivered to a 10 by 10 cm field that encompassed the rectal segment later to be resected and anastomosed (Figure 1). A deep tissue dose of 4,000 rads was delivered over a 4 week period with two treatments per week. At each treatment, equal doses were administered by way of the anterior and posterior ports using a 250 kV x-ray machine. Four weeks after the last irradiation dose, the dogs were prepared for surgery. A 3 day mechanical and oral antibiotic bowel preparation was performed. The dogs were begun on intramuscular Mandol preoperatively and continued receiving it for 3 days postoperatively. After induction of general anesthesia, laparotomy was performed and several centimeters of rectosigmoid colon was resected. The ends were reanastomosed using a disposable EEA-28 stapler (U.S. Surgical Corp., Stamford, CT). The resected colonic segment and the stapler “donuts” were retained for histological study. Three weeks later the dogs were sacrificed and autopsied. Those dogs that died before 3 weeks were autopsied at the time of death. The anastomoses were resected en bloc. All specimens were photographed and then studied histologically. An additional 15 dogs were likewise prepared for surgery. A low colorectal anastomosis was performed with an end-to-end stapling instrument. Three weeks postoperatively the dogs were sacrificed and autopsied.
Results
In the nonirradiated group there were no leaks or deaths. At the time of autopsy, all 15 dogs were noted to have well-healed anastomoses, both grossly and Material and Methods histologically. In the irradiated group of animals (15 Fifteen mongrel female dogs were obtained; all weighed dogs), 1 death occurred on the first postoperative day. between 40 and 50 pounds. After preliminary quarantine, At autopsy bilateral pneumonitis was noted, prevaccination, and parasite disinfest&ion, the dogs began a sumably related to the prolonged anesthesia that had been required. Two other deaths occurred during the Fmmtheoapa&MMofslrgety,cedars4inaiM3dkalctnlter,LosAngele9, casfomia. course of radiation. AlI three of these animals were Requestsfor reprints should be addressed to Leon Morgenstm. MD, deleted from our results, leaving 12 animals in the Depammnt of Surgery. Cedar&Sinai Medical Center, 8700 Beverly Sow irradiated group. Of these 12 irradiated animals, 4 hard, Los An~eles, California 90048. 246
The American Journal of SurQery
Preoperative Ir~adWon and lie&q o( A-
Aft%EtomoslSt
77 n
intact seawperforatlon
LdCWlthlll@CW-
Compleledlengtknm‘Thetwodogsthatdbddmtnglmdbtbn from an uretlmted came were ofnitted. ~Thek!0kageratewM66p4mm.
ii 3 2 alldthedogthatdbd
moses that were intact as contrasted with those that had leaked or undergone frank disruption. comments
died from 2 to 3 weeks postoperatively. All were found to have anastomotic leaks at autopsy. An additional 4 animals were found to have anastomotic leaks at autopsy, for a total of eight leaks in the irradiated group of 12 animals. Table I indicates the status of the irradiated anastornoses at autopsy. The overall leakage rate in irradiated anastomoses was 66 percent. Of the four anastomoses that were intact, two were noted to be ulcerated (Figure 2) and three to have microabscess formation in the wall. Thus, three of the four intact anastomoses demonstrated gross or histologic evidence of impaired healing. None of these animals died during the observation period. Three anastomoses had a localized area of perforation, but the perforations were sealed against the hollow of the sacrum (Figure 3, top). These perforations were 1 to 1.5 cm in diameter. Histologically, two of three of these anastomoses showed intramural microabscess formation (Figure 3, bottom). One of these three animals died during the observation period. In three animals, there was frank perforation of the anastomosis with extramural abscess formation. All of these anastomoses showed poor healing with intramural abscess formation and areas of ulceration. There was one death in this group. The remaining two animals had gross disruption of the entire suture line with pelvic or generalized peritonitis. Both animals died during the third week of observation. Microscopically, early changes of radiation injury were seen in all specimens. The submucosa showed the most marked changes, exhibiting edema, hyalinosis and thickening, with moderate ectasia of the submucoeal vessels. The mucosal changes were less marked, exhibiting varying degrees of hyperchromasia and nuclear irregularity at the base of the crypts. No correlation based on changes in histologic architecture could be made between those anastoVotwna 141, Fabmwy 1084
There is a scarcity of experimental studies on the healing of intestinal anastomoses in the irradiated intestine. Although Heupel et al [9] found no difference in the tensile strength of anastomoees in dogs after 1,500 rads of preoperative radiation as compared with nonirradiated control dogs, neither the amount of radiation nor the time of operation were
247
Morgenstern et al
comparable with those used seen in clinical practice. Crowley et al (101 studied the healing of small intestinal anastomoses in dogs after administering 1,500 rads preoperatively over a 10 day period. They also found no adverse effect on anastomotic healing, but their study also failed to simulate the amount of radiation or the radiation-operation sequence as practiced in a modem clinical setting. Our study was designed to simulate the most commonly employed type of preoperative radiation therapy as well as the time interval most commonly followed when perafter pelvic radiation for rectal carforming surgery cinoma. Clinical reports of healing of low rectal anastomoses after radiation are also sparse. Friedmann et al [8] described eight patients with colonic anastomoses in the field of radiation (4,000 to 4,500 rad tumor dose). There were two anastomotic leaks. Proximal transverse colostomies were used in all patients undergoing anterior resection. Stevens et al [2] described 13 patients irradiated with 5,000 rads
24s
for adenocarcinoma of the rectum and sigmoid who then underwent anterior resection and primary anastomosis. Anastomotic leaks developed in two of nine patients who had no protective colostomies. Four patients with protective colostomies had no anastomotic leakage. Schrock et al [II] reported anastomotic failure in 14.3 percent of 35 patients who had external radiation to the abdomen before operation as compared with a 4.6 percent failure rate in patients who had received no radiation. Since the introduction of the mechanical stapling device in the United States by Fain et al (121, there have as yet been no studies on the healing of low rectal anastomoses performed with the stapling instrument. Our study clearly denotes an adverse effect on anastomotic healing. The leakage rate of 66 percent was devastatingly high. Although anastomotic perforations were not lethal in all the animals, a septic or lethal complication occurred in more than half the animals who suffered anastomotic leaks. The inability to correlate the poor healing qualities of irradiated intestine with histologic findings is not surprising. Although the initial reaction to the amount of radiation is strikingly evident, sufficient reparation of irradiated intestine occurs within 4 weeks after irradiation so the histologic changes are rendered subtle or undiscernible. Late histopathologic changes occur months or years after irradiation. The effects of irradiation on collagen synthesis and collagen lysis are probably involved in the poor healing qualities of irradiated intestine. Hunt and Hawley [23] have described heightened collagenase levels and collagen lysis in colon injured in any manner. The clinical implications of this study are clear since we believe we may safely extrapolate from these experimental findings to the clinical situation. The low colorectal anastomosis performed on colon or rectum which has been irradiated at doses of 4,000 rads or higher is at great risk of dehiscence or disruption. Not only should such anastomoses be performed with meticulous technique, but all should be protected with a proximal colostomy. Since healing in irradiated tissue is slow and since radiation damage may be progressive, such protective colostomies should not be closed before a 3 month waiting period has elapsed. While the future of the preoperative radiation regimen for selected cases of rectal carcinoma is still uncertain, it is well to recognize the risks of anastomosis in those patients in whom it is employed. Summary The effect of preoperative irradiation on the healing of low colorectal anastomoses was studied experimentally. In 12 dogs in whom preoperative irradiation of 4,000 rads was given before low colorectal stapled anastomosis was performed, anastomotic leakage occurred in 66 percent. More than half rhaAvrmlunJounulor&wsoVr
Reoperative Irradiationand Wing
of the anastomotic leaks were associated with either severe sepsis or death. In a matched group of control animals that underwent stapled anastomoses without irradiation, no anastomotic complications occurred. The clinical implications of this study are that stapled anastomoses in irradiated colon are at serious risk of anastomotic dehiscence and, therefore, should be protected with a proximal colostomy. Acknowledgment: We thank Dr. Edgar Snow and Tom Patin of the Leo G. Rigler Radiological Research Facility at UCLA for their technical assistance, and Judi Lippe and James Rosenberg for their bibliographic research.
References 1. Stearns MW Jr, Deddish MR, Guan SHQ, Learning RH. Preoperative roentgen therapy for cancer of the rectum and rectosigmold. Surg Gynecol Dbstet 1974;138:584-6. 2. Stevens KR Jr, Fietcher WS, Allen CV. Anterior resection and primary anastomcsis following hi dose preoperative irradiation for adenocarcinorna of the recta-sigmoid. Cancer 1978;41:2065-71. 3. Kligerman MM, Urdaneta N, Knowlton A, Vidone R, Hartman PV, Vera R. Preoperative irradiation of rectosigmoid carcinoma including lts regional lymph nodes. Am J R 1972; 114498-503.
Volume 147, February lS04
of Anastomosee
4. Stevens KR Jr, Allen CV, Fletcher WS. Preoperative radiotherapy for adenccarcinoma of the rectcstgmbid. Cancer 1976$7:2866-74. 5. Higgins GA Jr, Conn JH, Jordan PH Jr, Humphrey EW, RoswK B; Keehn RJ. Preoperative radiotherapy for colorectal cancer. Ann Surg 1975;181:624-31. 6. Goligher JC, Greham NG, DeDombeI FT. Anastomotic dehlscence after anterior resection of rectum and sigmofd. Br J Surg 1970:57:109-18. 7. Mcrgenstem L, Yamakawa T, Ben-Shoshan M, Lippman H. Ana&motic leakage after low co&& +asbme&: clinical and experimental aspects. Am J Surg 1972; 123: 104-9. 8. Friedmann P, Park WC, Afonya II, et al. Adjuwint radfatfon tly;y in colorectal carcinoma. Am J Surg 1978;135: 9. Heupel RW, Veinbergs A, Humphrey EW. The effect of preoperative roentgen tfrerapy upon the tensile strength of rectosigmold anastomoses in dogs. Radicl Clin Ncrth Am 1966;35: 129-40. 10. Crowley LG, Anders CJ, Nelsen T, Bag&raw M. Effect of radiation on canine intestinal anastomoses. Arch Surg 1968;96:423-8. 11. Scfvock TR, Deveney CW, Dunphy JE. Factors conMbutlng to leakage of colonic anastomoses. Ann Surg 1973;177: 513-8. 12. FainSN,PatinCS,MorgenstemL.UaeofamedgnicalsuMng apparatus in low colorectal anastomosfs. Arch Surg 1975;110:1079-82. 13. Hunt TK, Hawley PR. Surgical judgment and colonic anastcb moses. Dis Colon Rectum 1969;12:167-71.
249
Leon Morgenstern,MD, FACS, Los Angeles, California George Sanders, MD, Los Angeles, California Erlk Wahlstrom,MD, Los Angeles, California Joseph Yadegar, MD, Los Angeles, California Pamela Amodeo, MA, Los Angeles, California
The role of preoperative irradiation followed by operative resection in the treatment of rectal carcinoma is a subject of current evaluation and controversy [l-3]. Proponents of routine preoperative irradiation for low lying rectal carcinoma claim to have shown that such treatment enhances survival statistics and should be used adjunctively before operation when cure is the objective [4,5]. Surgeons, however, fear the
adverse effects of such pretreatment, the most important of which is the effect on anastomotic healing. Not only is the lower rectum a formidable area from the technical points of access and maneuverability, but its tendency toward poor anastomotic healing is equally notorious [6,7]. In early clinical studies of routine preoperative irradiation, no increase in operative morbidity or mortality was reported [3]. The operations performed, however, were primarily abdominoperineal resections. In several recent studies [2,8], a high incidence of anastomotic leakage has been reported when a low anterior resection was performed after preoperative irradiation. To study the effect of preoperative irradiation on the healing of low colorectal anastomoses in a controlled fashion, we administered high-dose rectosigmoid irradiation to dogs. The dosage schedule was patterned after that used in clinical practice by Stevens et al [2] and Kligerman et al [3]. All anastomoses were studied at the time of death.
course of external beam irradiation to the lower midabdomen and pelvis. The irradiation was delivered to a 10 by 10 cm field that encompassed the rectal segment later to be resected and anastomosed (Figure 1). A deep tissue dose of 4,000 rads was delivered over a 4 week period with two treatments per week. At each treatment, equal doses were administered by way of the anterior and posterior ports using a 250 kV x-ray machine. Four weeks after the last irradiation dose, the dogs were prepared for surgery. A 3 day mechanical and oral antibiotic bowel preparation was performed. The dogs were begun on intramuscular Mandol preoperatively and continued receiving it for 3 days postoperatively. After induction of general anesthesia, laparotomy was performed and several centimeters of rectosigmoid colon was resected. The ends were reanastomosed using a disposable EEA-28 stapler (U.S. Surgical Corp., Stamford, CT). The resected colonic segment and the stapler “donuts” were retained for histological study. Three weeks later the dogs were sacrificed and autopsied. Those dogs that died before 3 weeks were autopsied at the time of death. The anastomoses were resected en bloc. All specimens were photographed and then studied histologically. An additional 15 dogs were likewise prepared for surgery. A low colorectal anastomosis was performed with an end-to-end stapling instrument. Three weeks postoperatively the dogs were sacrificed and autopsied.
Results
In the nonirradiated group there were no leaks or deaths. At the time of autopsy, all 15 dogs were noted to have well-healed anastomoses, both grossly and Material and Methods histologically. In the irradiated group of animals (15 Fifteen mongrel female dogs were obtained; all weighed dogs), 1 death occurred on the first postoperative day. between 40 and 50 pounds. After preliminary quarantine, At autopsy bilateral pneumonitis was noted, prevaccination, and parasite disinfest&ion, the dogs began a sumably related to the prolonged anesthesia that had been required. Two other deaths occurred during the Fmmtheoapa&MMofslrgety,cedars4inaiM3dkalctnlter,LosAngele9, casfomia. course of radiation. AlI three of these animals were Requestsfor reprints should be addressed to Leon Morgenstm. MD, deleted from our results, leaving 12 animals in the Depammnt of Surgery. Cedar&Sinai Medical Center, 8700 Beverly Sow irradiated group. Of these 12 irradiated animals, 4 hard, Los An~eles, California 90048. 246
The American Journal of SurQery
Preoperative Ir~adWon and lie&q o( A-
Aft%EtomoslSt
77 n
intact seawperforatlon
LdCWlthlll@CW-
Compleledlengtknm‘Thetwodogsthatdbddmtnglmdbtbn from an uretlmted came were ofnitted. ~Thek!0kageratewM66p4mm.
ii 3 2 alldthedogthatdbd
moses that were intact as contrasted with those that had leaked or undergone frank disruption. comments
died from 2 to 3 weeks postoperatively. All were found to have anastomotic leaks at autopsy. An additional 4 animals were found to have anastomotic leaks at autopsy, for a total of eight leaks in the irradiated group of 12 animals. Table I indicates the status of the irradiated anastornoses at autopsy. The overall leakage rate in irradiated anastomoses was 66 percent. Of the four anastomoses that were intact, two were noted to be ulcerated (Figure 2) and three to have microabscess formation in the wall. Thus, three of the four intact anastomoses demonstrated gross or histologic evidence of impaired healing. None of these animals died during the observation period. Three anastomoses had a localized area of perforation, but the perforations were sealed against the hollow of the sacrum (Figure 3, top). These perforations were 1 to 1.5 cm in diameter. Histologically, two of three of these anastomoses showed intramural microabscess formation (Figure 3, bottom). One of these three animals died during the observation period. In three animals, there was frank perforation of the anastomosis with extramural abscess formation. All of these anastomoses showed poor healing with intramural abscess formation and areas of ulceration. There was one death in this group. The remaining two animals had gross disruption of the entire suture line with pelvic or generalized peritonitis. Both animals died during the third week of observation. Microscopically, early changes of radiation injury were seen in all specimens. The submucosa showed the most marked changes, exhibiting edema, hyalinosis and thickening, with moderate ectasia of the submucoeal vessels. The mucosal changes were less marked, exhibiting varying degrees of hyperchromasia and nuclear irregularity at the base of the crypts. No correlation based on changes in histologic architecture could be made between those anastoVotwna 141, Fabmwy 1084
There is a scarcity of experimental studies on the healing of intestinal anastomoses in the irradiated intestine. Although Heupel et al [9] found no difference in the tensile strength of anastomoees in dogs after 1,500 rads of preoperative radiation as compared with nonirradiated control dogs, neither the amount of radiation nor the time of operation were
247
Morgenstern et al
comparable with those used seen in clinical practice. Crowley et al (101 studied the healing of small intestinal anastomoses in dogs after administering 1,500 rads preoperatively over a 10 day period. They also found no adverse effect on anastomotic healing, but their study also failed to simulate the amount of radiation or the radiation-operation sequence as practiced in a modem clinical setting. Our study was designed to simulate the most commonly employed type of preoperative radiation therapy as well as the time interval most commonly followed when perafter pelvic radiation for rectal carforming surgery cinoma. Clinical reports of healing of low rectal anastomoses after radiation are also sparse. Friedmann et al [8] described eight patients with colonic anastomoses in the field of radiation (4,000 to 4,500 rad tumor dose). There were two anastomotic leaks. Proximal transverse colostomies were used in all patients undergoing anterior resection. Stevens et al [2] described 13 patients irradiated with 5,000 rads
24s
for adenocarcinoma of the rectum and sigmoid who then underwent anterior resection and primary anastomosis. Anastomotic leaks developed in two of nine patients who had no protective colostomies. Four patients with protective colostomies had no anastomotic leakage. Schrock et al [II] reported anastomotic failure in 14.3 percent of 35 patients who had external radiation to the abdomen before operation as compared with a 4.6 percent failure rate in patients who had received no radiation. Since the introduction of the mechanical stapling device in the United States by Fain et al (121, there have as yet been no studies on the healing of low rectal anastomoses performed with the stapling instrument. Our study clearly denotes an adverse effect on anastomotic healing. The leakage rate of 66 percent was devastatingly high. Although anastomotic perforations were not lethal in all the animals, a septic or lethal complication occurred in more than half the animals who suffered anastomotic leaks. The inability to correlate the poor healing qualities of irradiated intestine with histologic findings is not surprising. Although the initial reaction to the amount of radiation is strikingly evident, sufficient reparation of irradiated intestine occurs within 4 weeks after irradiation so the histologic changes are rendered subtle or undiscernible. Late histopathologic changes occur months or years after irradiation. The effects of irradiation on collagen synthesis and collagen lysis are probably involved in the poor healing qualities of irradiated intestine. Hunt and Hawley [23] have described heightened collagenase levels and collagen lysis in colon injured in any manner. The clinical implications of this study are clear since we believe we may safely extrapolate from these experimental findings to the clinical situation. The low colorectal anastomosis performed on colon or rectum which has been irradiated at doses of 4,000 rads or higher is at great risk of dehiscence or disruption. Not only should such anastomoses be performed with meticulous technique, but all should be protected with a proximal colostomy. Since healing in irradiated tissue is slow and since radiation damage may be progressive, such protective colostomies should not be closed before a 3 month waiting period has elapsed. While the future of the preoperative radiation regimen for selected cases of rectal carcinoma is still uncertain, it is well to recognize the risks of anastomosis in those patients in whom it is employed. Summary The effect of preoperative irradiation on the healing of low colorectal anastomoses was studied experimentally. In 12 dogs in whom preoperative irradiation of 4,000 rads was given before low colorectal stapled anastomosis was performed, anastomotic leakage occurred in 66 percent. More than half rhaAvrmlunJounulor&wsoVr
Reoperative Irradiationand Wing
of the anastomotic leaks were associated with either severe sepsis or death. In a matched group of control animals that underwent stapled anastomoses without irradiation, no anastomotic complications occurred. The clinical implications of this study are that stapled anastomoses in irradiated colon are at serious risk of anastomotic dehiscence and, therefore, should be protected with a proximal colostomy. Acknowledgment: We thank Dr. Edgar Snow and Tom Patin of the Leo G. Rigler Radiological Research Facility at UCLA for their technical assistance, and Judi Lippe and James Rosenberg for their bibliographic research.
References 1. Stearns MW Jr, Deddish MR, Guan SHQ, Learning RH. Preoperative roentgen therapy for cancer of the rectum and rectosigmold. Surg Gynecol Dbstet 1974;138:584-6. 2. Stevens KR Jr, Fietcher WS, Allen CV. Anterior resection and primary anastomcsis following hi dose preoperative irradiation for adenocarcinorna of the recta-sigmoid. Cancer 1978;41:2065-71. 3. Kligerman MM, Urdaneta N, Knowlton A, Vidone R, Hartman PV, Vera R. Preoperative irradiation of rectosigmoid carcinoma including lts regional lymph nodes. Am J R 1972; 114498-503.
Volume 147, February lS04
of Anastomosee
4. Stevens KR Jr, Allen CV, Fletcher WS. Preoperative radiotherapy for adenccarcinoma of the rectcstgmbid. Cancer 1976$7:2866-74. 5. Higgins GA Jr, Conn JH, Jordan PH Jr, Humphrey EW, RoswK B; Keehn RJ. Preoperative radiotherapy for colorectal cancer. Ann Surg 1975;181:624-31. 6. Goligher JC, Greham NG, DeDombeI FT. Anastomotic dehlscence after anterior resection of rectum and sigmofd. Br J Surg 1970:57:109-18. 7. Mcrgenstem L, Yamakawa T, Ben-Shoshan M, Lippman H. Ana&motic leakage after low co&& +asbme&: clinical and experimental aspects. Am J Surg 1972; 123: 104-9. 8. Friedmann P, Park WC, Afonya II, et al. Adjuwint radfatfon tly;y in colorectal carcinoma. Am J Surg 1978;135: 9. Heupel RW, Veinbergs A, Humphrey EW. The effect of preoperative roentgen tfrerapy upon the tensile strength of rectosigmold anastomoses in dogs. Radicl Clin Ncrth Am 1966;35: 129-40. 10. Crowley LG, Anders CJ, Nelsen T, Bag&raw M. Effect of radiation on canine intestinal anastomoses. Arch Surg 1968;96:423-8. 11. Scfvock TR, Deveney CW, Dunphy JE. Factors conMbutlng to leakage of colonic anastomoses. Ann Surg 1973;177: 513-8. 12. FainSN,PatinCS,MorgenstemL.UaeofamedgnicalsuMng apparatus in low colorectal anastomosfs. Arch Surg 1975;110:1079-82. 13. Hunt TK, Hawley PR. Surgical judgment and colonic anastcb moses. Dis Colon Rectum 1969;12:167-71.
249