The Effects of Intraperitoneal 5-Fluorouracil Use at Different Doses on the Recovery Time of Experimental Intestinal Anastomoses

Yıl 2020, Sayı: 12, 310 - 325, 29.12.2020

Veysi Hakan Yardımcı

https://doi.org/10.38079/igusabder.731424

Öz

Aim: The most important complication of colorectal surgery is the separation of anastomosis or leakage. It is known that many local and systemic factors are effective in the healing process of colon anastomoses and in the formation of anastomotic leaks. One of these factors is chemotherapy. In order to achieve successful results in gastrointestinal system cancers, it is necessary to find the sensitive balance between the surgical method and chemotherapy and radiotherapy. 

Method: In our study, intraperitoneal administration of the most commonly used cytostatic 5-Fluorouracil (5-FU) in gastrointestinal tract cancers was investigated. For this purpose, 42 female Wistar Albino rats were divided into three main groups, each containing an equal number of subjects. Groups are Control group (Intraperitoneal NaCl), single dose 5-Fluorouracil group (Intraperitoneal 20 mg/kg/day 5-FU) and multiple dose 5-Fluorouracil group (Intraperitoneal 20 mg/kg/day 5-FU 3 days consecutively). Half of the 14 subjects in each main group were sacrificed on the 3rd day and the other half on the 7th day. Leukocyte and Albümin values were investigated for the purpose of examining the side effects of 5-FU. Bursting pressure, hydroxyproline level and histopathologic parameters were used to assess the differences in anastomotic healing between groups.

Results: There was no statistically significant difference in comparison with the control group of the chemotherapeutic 5-FU application in terms of intra-abdominal adhesions after surgical intervention (p>0,05). Albümin and leukocyte values; According to the control groups, statistically significant low results were obtained in groups used in 5-FU (p<0,05). Bursting pressure, histopathologic examination results in the evaluation of anastomotic healing; Multiple doses of 5-FU showed statistically significant low scores in groups with a single dose of 5-FU and control groups (p<0,05).

Conclusion: The impression obtained from the study showed that the high dose intraperitoneal 5-FU treatment, which was started in the early postoperative period, had a negative effect by delaying the anastomotic healing, but in limited doses Intraperitoneal 5-FU does not show any negative effects on anastomotic healing and is in parallel with control groups. In the light of this data from our experimental work; In clinical practice, it can be said that the chemotherapy, which has been feared and started late, may also find the usage area in the early postoperative period in limited doses.

Anahtar Kelimeler

5-Fluorouracil, anastomosis, regional perfusion cancer chemotherapy

Farklı Dozlarda Intraperitoneal 5-Fluorouracil Kullanımının Deneysel Intestinal Anastomozların İyileşme Süresi Üzerine Etkileri

Öz

Amaç: Kolorektal cerrahinin en önemli komplikasyonu anastomoz ayrılması veya kaçaktır. Lokal ve sistemik pek çok faktörün kolon anastomozlarının iyileşme sürecinde ve anastomoz kaçaklarının oluşmasında etkili olduğu bilinmektedir. Bu faktörlerden bir tanesi de kemoterapidir. Gastrointestinal sistem kanserlerinde başarılı sonuçlar alabilmek için cerrahi yöntem ile kemoterapi ve radyoterapi arasındaki hassas dengeyi bulabilmek şarttır.

Yöntem: Çalışmada gastrointestinal sistem (GİS) kanserlerinde en çok kullanılan sitostatik 5-Fluorouracil (5-FU) intraperitoneal uygulanması araştırılmıştır. Bu amaçla 42 adet Wistar Albino cinsi dişi sıçan her biri eşit sayıda denek içeren kontrol grubu (Intraperitoneal NaCl), tek doz 5-Fluorouracil grubu (Intraperitoneal 20 mg/kg/gün 5-FU) ve multipl doz 5-Fluorouracil grubu (Intraperitoneal 20 mg/kg/gün 5-FU 3 gün art arda) olmak üzere üç ana gruba ayrılmıştır. Her ana gruptaki 14 deneğin yarısı 3. günde, diğer yarısı ise 7. günde sakrifiye edilerek alt gruplar elde edilmiştir. 5-FU'in yan etkilerini incelemek amacıyla lökosit ve albümin değerleri araştırılmıştır. Anastomoz iyileşmesinin gruplar arasındaki farklılıklarını değerlendirmek için ise patlama basıncı, hidroksiprolin düzeyi ve histopatolojik parametreler kullanılmıştır.

Bulgular: Cerrahi girişim sonrası batın içi yapışıklıklar açısından 5-FU uygulamasının kontrol grubu ile karşılaştırılmasında istatistiksel açıdan anlamlı fark bulunmadı (p> 0,05). Albümin ve lökosit değerlerinde; kontrol gruplarına göre 5-FU kullanılan gruplarda istatistiksel olarak anlamlı düşük sonuçlar elde edildi (p<0,05). Anastomoz iyileşmesinin değerlendirilmesinde patlama basıncı, histopatolojik inceleme sonuçları multipl doz 5-FU kullanılan gruplarda tek doz 5-FU ve kontrol gruplarına göre istatistiksel olarak anlamlı düşük skorlar gösterdi (p<0,05).

Sonuç: Erken postoperatif dönemde başlanan multipl olarak verilen yüksek doz intraperitoneal 5-FU tedavisinin anastomoz iyileşmesini geciktirerek negatif etki gösterdiği, buna karşın sınırlı dozlarda uygulanan intraperitoneal 5-FU'in anastomoz iyileşmesi üzerinde hiçbir negatif etki göstermeyip kontrol grupları ile paralel iyileşme gösterdiği yönündedir. Deneysel çalışmadan elde edilen bu veriler ışığında; klinik uygulamada şimdiye kadar korkulan ve geç başlanan kemoterapinin, sınırlı dozlarda erken postoperatif dönemde de kullanım alanı bulabileceği söylenebilir.

Anahtar Kelimeler

5-Florourasil, anastomoz, bölgesel perfüzyon kanser kemoterapisi

Kaynakça

• Cunliffe WJ, Sugarbaker PH. Gastrointestinal malignancy: rationale for adjuvant therapy using early postoperative intraperitoneal chemotherapy. British Journal of Surgery. 1989;76(10):1082‐1090. doi:10.1002/bjs.1800761030.
• Hillan K, Nordlinger B, Ballet F, Puts JP, Infante R. The healing of colonic anasto-moses after early intraperitoneal chemotherapy: an experimental study in rats. Journal of Surgical Research. 1988;44(2):166‐171. doi:10.1016/0022-4804(88)90045-5.
• Hohenberger P, Schlag P, Schwarz V, Herfarth C. Tumor recurrence and options for further treatment after resection of liver metastases in patients with colorectal cancer. Journal of Surgical Oncology. 1990;44(4):245‐251. doi:10.1002/jso.2930440411.
• Metzger U, Mermillod B, Aeberhard P, et al. Intraportal chemotherapy in colorectal carcinoma as an adjuvant modality. World Journal of Surgery. 1987;11(4):452‐458. doi:10.1007/BF01655809.
• Sugarbaker PH, Gianola FJ, Barofsky I, Hancock SL, Wesley R. 5-Fluorouracil chemotherapy and pelvic radiation in the treatment of large bowel cancer. Decreased toxicity in combined treatment with 5-fluorouracil administration through the intraperitoneal route. Cancer. 1986;58(4):826‐831. doi:10.1002/1097-0142(19860815)58:4<826::aid-cncr2820580403>3.0.co;2-o.
• Falcone RE, Nappi JF. Chemotherapy and wound healing. Surgical Clinics of North America. 1984;64(4):779‐794. doi:10.1016/s0039-6109(16)43394-3.
• Klausner JM, Lelcuk S, Inbar M, Rozin R. The effects of perioperative fluorouracil administration on convalescence and wound healing. Archives of Surgery. 1986;121(2):239‐242. doi:10.1001/archsurg.1986.01400020125017.
• Nissen-Meyer R, Kjellgren K, Malmio K, Månsson B, Norin T. Surgical adjuvant chemotherapy: results with one short course with cyclophosphamide after mastectomy for breast cancer. Cancer. 1978;41(6):2088‐2098. doi:10.1002/1097-0142(197806)41:6<2088::aid-cncr2820410604>3.0.co;2-j.
• Haskel CM. Principles of cancer chemotherapy in: cancer treatment. 2nd ed. Philadelphia: WB Saunders Co.; 1985.
• Cohn I Jr. Complications and toxic manifestations of surgical adjuvant chemotherapy for breast cancer. Surgery, Gynecology and Obstetrics. 1968;127(6):1201‐1209.
• Lawrence WT, Talbot TL, Norton JA. Preoperative or postoperative doxorubicin hydrochloride (adriamycin): which is better for wound healing? Surgery. 1986;100(1):9‐13.
• Cohen SC, Gabelnick HL, Johnson RK, Goldin A. Effects of antineoplastic agents on wound healing in mice. Surgery. 1975;78(2):238‐244.
• De Roy van Zuidewijn DB, Wobbes T, Hendriks T, Klompmakers AA, de Boer HM. The effect of antineoplastic agents on the healing of small intestinal anastomoses in the rat. Cancer. 1986;58(1):62‐66. doi:10.1002/1097-0142(19860701)58:1<62::aid-cncr2820580112>3.0.co;2-x.
• De Waard JW, Wobbes T, Hendriks T. Early post-operative 5-fluorouracil does not affect the healing of experimental intestinal anastomoses. International Journal of Colorectal Disease. 1993;8(3):175‐178. doi:10.1007/BF00341194.
• Fumagalli U, Trabucchi E, Soligo M, et al. Effects of intraperitoneal chemotherapy on anastomotic healing in the rat. Journal of Surgical Research. 1991;50(1):82‐87. doi:10.1016/0022-4804(91)90014-d
• Berberoğlu U, Erekul S, Akbay C, Sayın N, Töral D, Sezerdoğdu V. Antimetabolit grubu kemoterapötiklerin yara iyileşmesine etkileri. Ulusal Cerrahi Dergisi. 1989;5(3):11-14.
• Matheson NA, Irving AD. Single layer anastomosis in the gastrointestinal tract. Surgery, Gynecology and Obstetrics. 1976;143(4):619‐624.
• Jiborn H, Ahonen J, Zederfeldt B. Healing of experimental colonic anastomoses. The effect of suture technic on collagen concentration in the colonic wall. American Journal of Surgery. 1978;135(3):333‐340. doi:10.1016/0002-9610(78)90062-4.
• Weiber S, Jiborn H, Zederfeldt B. Preoperative irradiation and colonic healing. European Journal of Surgery. 1994;160(1):47‐51.
• Beahrs OH. Continent ileostomy and ileoanal procedures. Surgical Clinics of North America. 1986;66(4):833‐839. doi:10.1016/s0039-6109(16)43994-0.
• Rousselot LM, Slattery JR. Immediate complications of surgery of the large intestine. Surgical Clinics of North America. 1964;44:397-410. doi:10.1016/s0039-6109(16)37238-3.
• Goligher JC, Graham NG, De Dombal FT. Anastomotic dehiscence after anterior resection of rectum and sigmoid. British Journal of Surgery. 1970;57(2):109‐118. doi:10.1002/bjs.1800570208.
• Morgenstern L, Yamakawa T, Ben-Shoshan M, Lippman H. Anastomotic leakage after low colonic anastomosis. Clinical and experimental aspects. American Journal of Surgery. 1972;123(1):104‐109. doi:10.1016/0002-9610(72)90317-0.
• Matheson NA, Irving AD. Single layer anastomosis after rectosigmoid resection. British Journal of Surgery. 1975;62(3):239‐242. doi:10.1002/bjs.1800620318.
• Dinççağ A, Erbil Y, Şerbetçioğlu A, Bozbora A, Özarmağan S, Mercan S. İntraperitoneal kemoterapi. Çağdaş Cerrahi Dergisi. 1993;7:98-100.
• Archer S, Gray B. Intraperitoneal 5-fluorouracil infusion for treatment of both peritoneal and liver micrometastases. Surgery. 1990;108(3):502‐507.
• Sugarbaker PH. Intraperitoneal chemotherapy for treatment and prevention of peritoneal carcinomatosis and sarcomatosis. Diseases of the Colon and Rectum. 1994;37(2):115-122. doi:10.1007/BF02048443.
• Sugarbaker PH, Gianola FJ, Speyer JC, Wesley R, Barofsky I, Meyers CE. Prospective, randomized trial of intravenous versus intraperitoneal 5-fluorouracil in patients with advanced primary colon or rectal cancer. Surgery. 1985;98(3):414‐422.
• Goldman LI, Lowe S, al-Saleem T. Effect of fluorouracil on intestinal anastomoses in the rat. Archives of Surgery. 1969;98(3):303‐304. doi:10.1001/archsurg.1969.01340090079011.
• Graf W, Ivarsson M, Gerdin B, Hellsing K, Påhlman L, Glimelius B. The influence of early postoperative intraperitoneal chemotherapy on human wound healing. Journal of Surgical Research. 1994;57(3):394‐400. doi:10.1006/jsre.1994.1160.
• Graf W, Weiber S, Glimelius B, Jiborn H, Påhlman L, Zederfeldt B. Influence of 5-fluorouracil and folinic acid on colonic healing: an experimental study in the rat. British Journal of Surgery. 1992;79(8):825‐828. doi:10.1002/bjs.1800790840.
• Taylor I, Machin D, Mullee M, Trotter G, Cooke T, West C. A randomized controlled trial of adjuvant portal vein cytotoxic perfusion in colorectal cancer. British Journal of Surgery. 1985;72(5):359‐363. doi:10.1002/bjs.1800720509.
• Erdener A, Çetinkurşun S, Avanoğlu A ve ark. İntraperitoneal adjuvan 5-DFUR' in sıçan kolon anastomozunda iyileşmeye etkisi. Ulusal Cerrahi Dergisi. 1990;6(3):25-27.