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Lambrou I, Mantzoros I, Ioannidis O, Tatsis D, Anestiadou E, Bisbinas V, Pramateftakis MG, Kotidis E, Driagka B, Kerasidou O, Symeonidis S, Bitsianis S, Sifaki F, Angelopoulos K, Demetriades H, Angelopoulos S. Effect of growth hormone on colonic anastomosis after intraperitoneal administration of 5-fluorouracil, bleomycin and cisplatin: An experimental study. World J Gastrointest Surg 2024; 16:2679-2688. [PMID: 39220091 PMCID: PMC11362934 DOI: 10.4240/wjgs.v16.i8.2679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 05/20/2024] [Accepted: 06/17/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND Growth hormone (GH) plays a crucial role in wound healing and tissue repair in postoperative patients. In particular, colonic anastomosis healing following colorectal surgery is impaired by numerous chemotherapy agents. AIM To investigate whether GH can improve the healing of a colonic anastomosis following the adverse effects of intraperitoneal administration of 5-fluorouracil (5-FU), bleomycin and cisplatin. METHODS Eighty Wistar rats underwent laparotomy and a 1 cm-resection of the transverse colon, followed by an end-to-end anastomosis under general anesthesia. The rats were blindly allocated into four equal groups and administered a different daily intraperitoneal therapeutic regimen for 6 days. The control group (A) received normal saline. Group B received chemotherapy with 5-FU (20 mg/kg), bleomycin (4 mg/kg) and cisplatin (0.7 mg/kg). Group C received GH (2 mg/kg), and group D received the aforementioned combination chemotherapy and GH, as described. The rats were sacrificed on the 7th postoperative day and the anastomoses were macroscopically and microscopically examined. Body weight, bursting pressure, hydroxyproline levels and inflammation markers were measured. RESULTS All rats survived until the day of sacrifice, with no infections or other complications. A decrease in the body weight of group D rats was observed, not statistically significant compared to group A (P = 1), but significantly different to groups C (P = 0.001) and B (P < 0.01). Anastomotic dehiscence rate was not statistically different between the groups. Bursting pressure was not significantly different between groups A and D (P = 1.0), whereas group B had a significantly lower bursting pressure compared to group D (P < 0.001). All groups had significantly more adhesions than group A. Hydroxyproline, as a measurement of collagen deposition, was significantly higher in group D compared to group B (P < 0.05), and higher, but not statistically significant, compared to group A. Significant changes in group D were recorded, compared to group A regarding inflammation (3.450 vs 2.900, P = 0.016) and fibroblast activity (2.75 vs 3.25, P = 0.021). Neoangiogenesis and collagen deposition were not significantly different between groups A and D. Collagen deposition was significantly increased in group D compared to group B (P < 0.001). CONCLUSION Intraperitoneal administration of chemotherapy has an adverse effect on the healing process of colonic anastomosis. However, GH can inhibit the deleterious effect of administered chemotherapy agents and induce colonic healing in rats.
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Affiliation(s)
- Ioannis Lambrou
- Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece
| | - Ioannis Mantzoros
- Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece
| | - Orestis Ioannidis
- Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece
| | - Dimitrios Tatsis
- Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece
| | - Elissavet Anestiadou
- Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece
| | - Vasiliki Bisbinas
- Department of ENT, Royal Cornwall Hospitals NHS Trust, Cornwall TR1 3LJ, United Kingdom
| | | | - Efstathios Kotidis
- Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece
| | - Barbara Driagka
- Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece
| | - Ourania Kerasidou
- Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece
| | - Savvas Symeonidis
- Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece
| | - Stefanos Bitsianis
- Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece
| | - Freideriki Sifaki
- Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece
| | - Konstantinos Angelopoulos
- Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece
| | - Haralabos Demetriades
- Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece
| | - Stamatios Angelopoulos
- Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece
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Cascinu S, Valentini G, Catalano G. A Pilot Clinical Trial of Postoperative Adjuvant Intraperitoneal Cisplatin, 5-Fluorouracil, 6S-Leucovorin and Interferon Alpha 2b in Patients with Resected Gastric Cancer. TUMORI JOURNAL 2018; 79:331-5. [PMID: 8116076 DOI: 10.1177/030089169307900509] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Aims and Background The study was performed to assess the toxicity and impact on relapse pattern of postoperative intraperitoneal cisplatin, 5-fluorouracil, leucovorin and interferon therapy as adjuvant treatment for gastric cancer patients who are at high risk for recurrence after potentially curative resection (T2 N1-2; T3-4 N any Mo). Patients and Methods Starting 14 to 21 days after potentially curative resection of primary gastric cancers, 22 patients were given intraperitoneal cisplatin, 60 mg/m2; 5-fluorouracil, 1000 mg/m2; 6S-leucovorin, 250 mg/m2; interferon alpha 2b, 10 MU/m2; every other week for six times. Results After a median follow-up of 24 months, 63 % of patients were alive and free of disease. Eight patients had recurred; five had an intraabdominal component, and 3 had extraabdominal failure. Toxicity was mild: no grade III-IV WHO toxicity was observed. Conclusions Intraperitoneal cisplatin, 5-fluorouracil, 6S-leucovorin and interferon is a tolerable therapy in the postoperative setting for patients with resected gastric cancer. These data make this approach interesting for the development of new programs of adjuvant therapy of high-risk gastric cancer.
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Affiliation(s)
- S Cascinu
- Servizio di Oncologia, Ospedali Riuniti, Pesaro, Italy
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Nerstrøm M, Krarup PM, Jorgensen LN, Ågren MS. Therapeutic improvement of colonic anastomotic healing under complicated conditions: A systematic review. World J Gastrointest Surg 2016; 8:389-401. [PMID: 27231518 PMCID: PMC4872068 DOI: 10.4240/wjgs.v8.i5.389] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 11/14/2015] [Accepted: 03/09/2016] [Indexed: 02/07/2023] Open
Abstract
AIM: To identify therapeutic agents for the prophylaxis of gastrointestinal anastomotic leakage (AL) under complicated conditions.
METHODS: The PubMed and EMBASE databases were searched for English articles published between January 1975 and September 2014. Studies with the primary purpose of improving anastomotic healing in the colon or rectum under complicated preoperative and/or intraoperative conditions were included. We excluded studies investigating the adverse effects or risk assessment of an active intervention. Furthermore, investigations of biophysical materials, sealants, electrical stimulation and nutrients were excluded. The primary study outcome was biomechanical anastomotic strength or AL. The meta-analysis focused on therapeutic agents that were investigated in one animal model using the same outcome by at least three independent research groups.
RESULTS: The 65 studies included were divided into 7 different complicated animal models: Bowel ischemia, ischemia/reperfusion, bowel obstruction, obstructive jaundice, peritonitis, chemotherapy and radiotherapy. In total, 48 different therapeutic compounds were examined. The majority of investigated agents (65%) were reported as beneficial for anastomotic healing. Twelve of the agents (25%) were tested more than once in the same model, whereas 13 (27%) of the agents were tested in two or more models of complicated healing. Two therapeutic agents met our inclusion criteria for the meta-analysis. Postoperative hyperbaric oxygen therapy significantly increased anastomotic bursting pressure in ischemic colon anastomoses by a mean of 28 mmHg (95%CI: 17 to 39 mmHg, P < 0.00001). Granulocyte macrophage-colony stimulating factor failed to show a significant increase in anastomotic bursting pressure (95%CI: -20 to 21 mmHg, P = 0.97) vs controls in experimental chemotherapeutic models.
CONCLUSION: This systematic review identified potential therapeutic agents, but more studies are needed before concluding that any of these are useful for AL prophylaxis.
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Blouhos K, Pramateftakis MG, Tsachalis T, Kanellos D, Zaraboukas T, Koliakos G, Betsis D. The integrity of colonic anastomoses following the intraperitoneal administration of oxaliplatin. Int J Colorectal Dis 2010; 25:835-41. [PMID: 20217424 DOI: 10.1007/s00384-010-0912-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/11/2010] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The purpose of this experimental study was to determine the effect of oxaliplatin on the integrity of colonic anastomoses which were under oxaliplatin administration. MATERIALS AND METHODS Thirty rats were randomized to two groups. After resection of a 1-cm segment of the transverse colon, an end-to-end sutured anastomosis was performed. Rats of the control group were injected with 3 ml of 0.9% sodium chloride solution and in the oxaliplatin group with 2.4 mg/kg of oxaliplatin intraperitoneally immediately after surgery and for seven postoperative days. All rats were sacrificed on the tenth postoperative day, and the anastomoses were examined macroscopically and graded histologically. Rats were measured for anastomotic bursting pressures and tissue hydroxyproline levels. RESULTS The body weight changes were significantly greater in the oxaliplatin group (p = 0.005). Anastomotic dehiscence occurred only in the oxaliplatin group. The adhesion formation was significantly increased in the group of oxaliplatin compared to the control group (p = 0.001). The colonic bursting pressure was significantly lower in the oxaliplatin group compared to the control group (p < 0.001). The mean inflammatory cell infiltration was significantly lower in the oxaliplatin group (1.00 vs. 2.33, p < 0.001). The mean neoagiogenesis was significantly lower in the oxaliplatin group (0.80 vs. 2.20, p < 0.001). The mean collagen deposition was significantly lower in the oxaliplatin group and the mean fibroblast activity was significantly lower in the oxaliplatin group (1.27 vs. 2.53, p < 0.001). Hydroxyproline concentration was significantly lower in the oxaliplatin group (p < 0.001). CONCLUSION Intra- and postoperative intraperitoneal administration of oxaliplatin definitely impairs healing of colonic anastomoses in rats.
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Affiliation(s)
- Konstantinos Blouhos
- Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
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Healing of colonic anastomoses after immediate postoperative intraperitoneal administration of oxaliplatin. Int J Colorectal Dis 2008; 23:1185-91. [PMID: 18677490 DOI: 10.1007/s00384-008-0538-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/03/2008] [Indexed: 02/04/2023]
Abstract
AIM The aim of this experimental study was to investigate the effect of intraperitoneal administration of oxaliplatin on the healing of colonic anastomoses when injected immediately after colon resection. MATERIALS AND METHODS Thirty male Wistar rats were used. During the operation, the rats were randomized to two groups of 15 rats each. Immediately after colonic anastomoses were performed, the rats were injected intraperitoneally with either 3 ml of 0.9% NaCl solution or oxaliplatin (2.4 mg/kg body weight) depending on their group. All rats were killed on the eighth postoperative day. The anastomoses were examined macroscopically. The anastomotic bursting pressures were recorded, the anastomoses graded histologically, and the hydroxyproline tissue contents determined. RESULTS Anastomotic leakage was noted in four rats (26.7%) of the oxaliplatin group, whereas no anastomotic dehiscence was detected among rats of the control group (p = 0.016). The adhesion formation at the anastomotic sites and the inflammatory cell infiltration were significantly higher in the oxaliplatin group than in the control group (p = 0.001). The bursting pressures (p = 0.001), the hydroxyproline tissue content (p = 0.001), the neoangiogenesis (p = 0.033), the fibroblast activity (p = 0.001), and the collagen deposition (p = 0.001) were significantly lower in the oxaliplatin group in comparison to the control group. CONCLUSION The immediate postoperative intraperitoneal administration of oxaliplatin seems to impair healing of colonic anastomoses in rats.
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Zacharakis E, Demetriades H, Pramateftakis MG, Lambrou I, Zacharakis E, Zaraboukas T, Koliakos G, Kanellos I, Betsis D. Effect of IGF-I on healing of colonic anastomoses in rats under 5-FU treatment. J Surg Res 2007; 144:138-44. [PMID: 17640667 DOI: 10.1016/j.jss.2007.03.045] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2006] [Revised: 01/29/2007] [Accepted: 03/19/2007] [Indexed: 01/02/2023]
Abstract
BACKGROUND The aim of this experimental study was to investigate whether insulin-like growth factor I (IGF-I) can protect the colonic healing from the adverse effects of intraperitoneal administration of 5-fluorouracil (5-FU). MATERIALS AND METHODS Eighty male Wistar rats were randomized into four groups of 20 rats each. Immediately after anastomoses were performed, rats in the control group were injected with 1 mL/100 gr of intraperitoneal saline solution, which was repeated daily until killed. Rats in the 5-FU and IGF-I +5-FU groups received 5-FU in a dose of 20 mg/kg body weight intraperitoneally, from the day of operation until killed. Rats in the IGF-I and IGF-I +5-FU groups received IGF-I in a dose of 2 mg/kg body weight intraperitoneally, immediately after the colonic anastomosis was performed and on 2nd, 4th, and 6th postoperative day. Rats were sacrificed on the 7th postoperative day. RESULTS The dehiscence rate in the 5-FU group was 30% and it was significantly higher compared with the control and the IGF-I group (P = 0.020 for both comparisons). However, in the IGF-I +5-FU group, the dehiscence rate decreased to 10%. The administration of IGF-I resulted in a significant rise of bursting pressure in the IGF-I +5-FU group compared with the 5-FU group (P < 0.001). There was no statistical difference in bursting pressure between the IGF-I +5-FU and control groups (P = 1.000). The hydroxyproline levels were higher in the IGF-I and the IGF-I +5-FU groups as a result of the stimulating act of IGF-I. CONCLUSION IGF-I, when given intraperitoneally, seems to mediate some of the adverse effects of 5-FU on the colonic healing in rats.
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Affiliation(s)
- Emmanouil Zacharakis
- 4th Academic Surgical Unit, Aristotle University of Thessaloniki, G. Papanikolaou General Hospital, Makedonia, Greece.
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Colak T, Dag A, Turkmenoglu O, Polat A, Comelekoglu U, Bagdatoglu O, Polat G, Akca T, Sucullu I, Aydin S. The effect of octreotide on healing of injured colonic anastomosis with immediate postoperative intraperitoneal administration of 5-Fluorouracil. Dis Colon Rectum 2007; 50:660-9. [PMID: 17216142 DOI: 10.1007/s10350-006-0810-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE This study was designed to investigate the effect of octreotide on side effects of immediate usage of 5-fluorouracil after colonic anastomosis. METHODS Forty male Wistar rats were randomly assigned into four groups and underwent standardized left colonic anastomosis. The rats served as control or received intraperitoneal 5-fluorouracil (20 mg/kg daily), subcutaneous octreotide (20 mug/kg daily), or both. Diarrhea and wound complications were noted during the experiment. The colonic anastomoses were assessed for healing on postoperative Day 7 by determining the anastomotic bursting pressure, performing histologic examination, and measuring the tissue hydroxyproline content, serum malondialdehyde, and nitric oxide levels. Intraperitoneal adhesions and anastomotic leakage were also noted. RESULTS No statistical significant difference was found between the control and octreotide groups for each of the parameters measured. Immediate 5-fluorouracil use resulted with higher adhesion score (P = 0.002), significant depression in anastomotic bursting pressure (P = 0.0001), histopathologic score (P = 0.0001), hydroxyproline content (P = 0.0001), and increasing nitric oxide (P = 0.0001) and malondialdehyde levels (P = 0.0001) compared with the control group. Diarrhea was seen in 80 percent of the 5-fluorouracil group but in neither the control nor octreotide groups (P = 0.0001 for each comparison). However, all these parameters were ameliorated by use of concomitant octreotide and 5-fluorouracil (P = 0.019, P = 0.023, P = 0.0001, P = 0.006, P = 0.0001, and P = 0.013, respectively). In addition, diarrhea was found to be prevented (P = 0.0001). CONCLUSIONS The results of this study showed that concomitant octreotide use might prevent the side effects of 5-fluorouracil, such as diarrhea, postoperative adhesion, and delaying the anastomotic healing parameters. In addition, it might reduce tissue damage and inflammation.
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Affiliation(s)
- Tahsin Colak
- Faculty of Medicine, Department of General Surgery, Mersin University, Tip Fakultesi Hastanesi, Zetinlibahce C., Mersin, 33097, Turkey.
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Fukuchi SG, Seeburger JL, Parquet G, Rolandelli RH. Influence of 5-fluorouracil on colonic healing and expression of transforming growth factor-beta 1. J Surg Res 1999; 84:121-6. [PMID: 10357907 DOI: 10.1006/jsre.1999.5626] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Administration of chemotherapeutic agents in the immediate postoperative period may have beneficial effects by decreasing local cancer recurrence rates, but this must be weighed against possible impairment of wound healing. Since local expression of transforming growth factor-beta1 (TGF-beta1) is normally upreglated following creation of experimental colonic anastomoses, this study examines the effects of 5-fluorouracil (5-FU) on colonic healing and on the local expression of TGF-beta1. MATERIALS AND METHODS Forty-eight male Sprague-Dawley rats underwent transection of the descending colon with primary anastomosis and were then randomly assigned to receive either intraperitoneal 5-FU (20 mg/kg/day) or saline (SAL). On Postoperative Days (PODs) 3, 5, and 7, bursting pressure (BP, mm Hg) and bursting energy (BE, mm Hg xs) were determined in situ. Anastomotic and nonoperated segments of colon were harvested and analyzed using the semiquantitative reverse transcriptase-polymerase chain reaction to determine the relative expression of TGF-beta1 normalized to that of a constitutive gene. RESULTS Progressive increases in BP and BE were observed in both the 5-FU and the SAL groups, across the time course examined. Overall, these measures were decreased in the 5-FU groups compared to SAL, significantly so on PODs 5 and 7; BP, 127.8 +/- 7.6 vs 161.1 +/- 7.2 and 139.9 +/- 10.9 vs 186.0 +/- 8.6; BE, 1093.6 +/- 190.0 vs 2207.9 +/- 308.2, and 1518.5 +/- 326.5 vs 3279.3 +/- 225.7, respectively. Anastomotic TGF-beta1 expression also increased progressively in both groups over the postoperative time course. Expression in the 5-FU group, however, was significantly decreased compared to that in the SAL group on POD 3; 0.42 +/- 0.05 vs 0.84 +/- 0.04. Interestingly, this preceded the reduction in BP and BE in the 5-FU group on PODs 5 and 7. TGF-beta1 expression in nonoperated colonic segments did not change during the time points studied or in response to 5-FU administration. CONCLUSIONS Wound healing following a colonic anastomosis is associated with local increases in TGF-beta1 expression, which in turn is diminished by the administration of 5-FU. If this deleterious effect on wound healing could be counteracted, then chemotherapy administration in the immediate postoperative period may become safer.
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Affiliation(s)
- S G Fukuchi
- Department of Surgery, MCP, Hahnemann University, Philadelphia, USA
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van der Kolk BM, de Man BM, Wobbes T, Hendriks T. Is early post-operative treatment with 5-fluorouracil possible without affecting anastomotic strength in the intestine? Br J Cancer 1999; 79:545-50. [PMID: 10027328 PMCID: PMC2362429 DOI: 10.1038/sj.bjc.6690086] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Early post-operative local or systemic administration of 5-fluorouracil (5-FU) is under investigation as a means to improve outcome after resection of intestinal malignancies. It is therefore quite important to delineate accurately its potentially negative effects on anastomotic repair. Five groups (n = 24) of rats underwent resection and anastomosis of both ileum and colon: a control group and four experimental groups receiving daily 5-FU, starting immediately after operation or after 1, 2 or 3 days. Within each group, the drug (or saline) was delivered either intraperitoneally (n = 12) or intravenously (n = 12). Animals were killed 7 days after operation and healing was assessed by measurement of anastomotic bursting pressure, breaking strength and hydroxyproline content. In all cases, 5-FU treatment from the day of operation or from day 1 significantly (P<0.025) and severely suppressed wound strength; concomitantly, the anastomotic hydroxyproline content was reduced. Depending on the location of the anastomosis and the route of 5-FU administration, even a period of 3 days between operation and first dosage seemed insufficient to prevent weakening of the anastomosis. The effects of intravenous administration, though qualitatively similar, were quantitatively less dramatic than those observed after intraperitoneal delivery. Post-operative treatment with 5-FU, if started within the first 3 days after operation, is detrimental to anastomotic strength and may compromise anastomotic integrity.
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Affiliation(s)
- B M van der Kolk
- Department of Surgery, University Hospital Nijmegen, The Netherlands
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Bostanoğlu S, Dinçer S, Keskin A, Bostanoğlu A, Dursun A, Serim C. Beneficial effect of Iloprost on impaired colonic anastomotic healing induced by intraperitoneal 5-fluorouracil infusion. Dis Colon Rectum 1998; 41:642-8. [PMID: 9593250 DOI: 10.1007/bf02235275] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE 5-Fluorouracil is the most effective chemotherapeutic agent in the management of patients with systemic colorectal cancer. Studies in recent years discussed the gradually increasing benefits of 5-fluorouracil within adjuvant chemotherapy protocols after complete surgical resections. However, many studies also have demonstrated that 5-fluorouracil impairs wound-healing on colonic anastomoses. METHODS In our experimental study, we examined the influence of intraperitoneal 5-fluorouracil on healing of colonic anastomoses and, also, attempted to discover whether Iloprost (PGI2 analog, a potent vasodilator with confirmed cytoprotectivity and inhibitor of thrombocyte aggregation) counteracts impaired wound-healing induced by 5-fluorouracil. A total of 80 Wistar-Albino male rats were separated into four groups. From the day of the operation, Group A received intraperitoneal saline solution, Group B received 20 mg/kg 5-fluorouracil intraperitoneally, Group C received 20 mg/kg 5-fluorouracil plus 2 microg/kg Iloprost intraperitoneally, and Group D received 2 microg/kg Iloprost intraperitoneally. Each group was divided into two subgroups, and both subgroups were killed on the third and seventh postoperative days, respectively. The subjects were measured for anastomose bursting pressures and tissue hydroxyproline levels, and wound-healing was evaluated histopathologically. Statistical evaluations among each group were made with Student's t-test and Pearson's chi-squared tests. RESULTS Iloprost had an accelerating effect on normal colonic anastomose wound-healing histopathologically, had no significant difference on bursting pressures and hydroxyproline levels, and significantly improved the impaired healing effect of 5-fluorouracil. CONCLUSIONS Our study showed a positive effect of Iloprost on the healing of colon anastomosis and, more importantly, if wound-healing is impaired by a chemotherapeutic agent, Iloprost counteracts and reverses the effect. [Key words: 5-Fluorouracil; Healing of colon anastomoses; Iloprost
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Affiliation(s)
- S Bostanoğlu
- 6th Department of Surgery, Ankara Numune Hospital, Turkey
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Penna C, Nordlinger B. Locoregional chemotherapy for adjuvant treatment of colorectal adenocarcinoma. Eur J Cancer 1996; 32A:1117-22. [PMID: 8758240 DOI: 10.1016/0959-8049(96)00044-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Adjuvant chemotherapy with 5-fluorouracil (5-FU) and levamisole administered intravenously for 1 year has proved to be effective after curative surgical resection of Dukes' stage C colon carcinomas. Locoregional chemotherapy aims at delivering drugs directly into the abdominal cavity or the liver using either intraperitoneal or intraportal route of administration. Theoretically, these routes of administration have several advantages. The drugs can be delivered at a high dose concentration to the most common site of recurrence (i.e. peritoneum and liver) with decreased systemic toxicity. This article reviews the present status of intraportal and intraperitoneal chemotherapy as adjuvant postoperative treatment for colorectal carcinoma with special attention to the results of prospective randomised trials. Some positive results confirm that both route of administration represent promising methods for adjuvant chemotherapy. However, currently there are insufficient data on which to make a clear-cut conclusion on real benefits. New trials are currently in progress to test new modalities using different drugs or different drug combinations, using both locoregional and systemic treatments, and may prove to be more effective than systemic chemotherapy alone in the adjuvant treatment of colorectal cancers.
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Affiliation(s)
- C Penna
- Department of Gastrointestinal Surgery, Hospital Saint-Antoine, Paris, France
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Hananel N, Gordon PH. Effect of 5-fluorouracil and leucovorin on the integrity of colonic anastomoses in the rat. Dis Colon Rectum 1995; 38:886-90. [PMID: 7634984 DOI: 10.1007/bf02049847] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
PURPOSE This study was designed to determine the effects of 5-fluorouracil and leucovorin on the healing of colonic anastomoses and assess the safety of conducting a colonic resection and anastomosis during and shortly after a course of this chemotherapy in a rat model. METHODS Fifty-six male Wistar rats, weighing 200 to 250 gm, were divided into four groups, each consisting of 14 animals. Animals in Group I (control group) underwent colon resection and primary anastomosis. Animals in Group II received 10 mg/kg intravenous 5-fluorouracil and 10 mg/kg leucovorin once a week for four weeks and then underwent the same operation. Animals in Groups III and IV received the same drug dosage for six weeks and were operated at different intervals: Group III at one week and Group IV at two weeks after completion of chemotherapy. Within each group, one-half of the animals were sacrificed on the third postoperative day and one-half on the seventh postoperative day, and anastomotic bursting pressure measurements were performed. RESULTS At three and seven days, mean bursting pressure of the anastomoses were determined: 98 mmHg and 180.7 mmHg in Group I, 95 and 197.8 in Group II, 85.7 and 189.2 in Group III, and 98.6 and 179.2 in Group IV, respectively. There was no significant difference in bursting pressure between treated animals and controls by the third postoperative day or by the seventh day. The burst occurred at the anastomosis in all specimens tested on the third postoperative day and in the bowel wall adjacent to the anastomosis in all specimens tested on the seventh postoperative day. CONCLUSION This study demonstrates that the above regimen of chemotherapy has no effect on the healing of colonic anastomoses and that surgery can be performed safely during and shortly after this regimen of chemotherapy.
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Affiliation(s)
- N Hananel
- Department of Surgery, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada
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de Waard JW, Wobbes T, de Man BM, van der Linden CJ, Hendriks T. Post-operative levamisole may compromise early healing of experimental intestinal anastomoses. Br J Cancer 1995; 72:456-60. [PMID: 7640232 PMCID: PMC2034010 DOI: 10.1038/bjc.1995.355] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
There exists growing interest in immediate post-operative local adjuvant therapy after resection of intestinal malignancies. It is therefore necessary to assess it potential effect on the healing of intestinal anastomoses. Five groups (n = 20) of rats underwent resection and anastomosis of both ileum and colon: a control group and four experimental groups receiving intraperitoneal 5-fluorouracil (5-FU), 5-FU plus leucovorin, 5-FU plus levamisole or levamisole alone, on the day of surgery and the next 2 days. Animals were killed 3 or 7 days after operation. Another three groups (n = 6) of animals were used to compare anastomotic collagen synthetic capacity in control rats or rats receiving 5-FU or 5-FU plus levamisole. On the third post-operative day, the average anastomotic bursting pressure in the 5-FU/levamisole group was reduced by 36% as compared with the control group, both in ileum (P = 0.02) and in colon (P = 0.01). Values in the other groups were similar to those in the control group. Anastomotic breaking strength was significantly (P < 0.025) lowered in the ileum from the levamisole group at both days 3 and 7. Anastomotic collagen synthetic capacity was strongly reduced in the 5-FU and 5-FU/levamisole groups. However, there was no significant difference between the control group and the four experimental groups with regard to anastomotic hydroxyproline concentration and content, either 3 or 7 days after operation. Thus, limited use of levamisole, alone or in combination with intraperitoneal 5-FU, may compromise intestinal healing.
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Affiliation(s)
- J W de Waard
- Department of Surgery, University Hospital Nijmegen, The Netherlands
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Graf W, Westlin JE, Påhlman L, Glimelius B. Adjuvant intraperitoneal 5-fluorouracil and intravenous leucovorin after colorectal cancer surgery: a randomized phase II placebo-controlled study. Int J Colorectal Dis 1994; 9:35-9. [PMID: 8027622 DOI: 10.1007/bf00304298] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Fifty patients were randomized to receive adjuvant intraperitoneal 5-fluorouracil (5-FU, 500 mg/m2/day) and intravenous leucovorin (60 mg/m2/day) and 51 to receive placebo after curative surgery for colorectal cancer. Treatment started on the day after surgery and continued for 6 days. One case of stomatitis, one of leucopenia and one case of abnormal liver function tests were the only chemotherapy-related toxic effects. From the second day of treatment, pain during intraperitoneal infusions occurred more frequently in the 5-FU group, although statistical significance was only attained on day 2 (P < 0.05). The groups did not differ substantially regarding any other adverse effects, the incidence of surgical complications, second laparotomies, time from surgery to discharge, or premature treatment terminations. The postoperative course after intraperitoneal 5-FU and intravenous leucovorin was thus not more complicated than that in patients treated with placebo. The tolerance was acceptable and chemotherapy-related toxicity was rare. Thus important prerequisites exist for more widespread use of the present regimen in order to evaluate its impact on survival.
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Affiliation(s)
- W Graf
- Department of Surgery, Akademiska Sjukhuset, Uppsala, Sweden
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de Waard JW, Wobbes T, Hendriks T. Early post-operative 5-fluorouracil does not affect the healing of experimental intestinal anastomoses. Int J Colorectal Dis 1993; 8:175-8. [PMID: 8245676 DOI: 10.1007/bf00341194] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
5-Fluorouracil (5-FU) remains the mainstay for systemic treatment of colorectal cancer. In view of the increasing interest in peri-operative administration of antineoplastic agents, we have investigated the effects of early postoperative 5-FU on the healing of intestinal anastomoses in the rat. Animals underwent resection and anastomosis of both ileum and colon and 5-FU (20 mg/kg body weight) was given, either intravenously or intraperitoneally, on the day of surgery and the two subsequent days. Healing was assessed three and seven days after operation. Administration of 5-FU led to a reduced white blood cell count. However, anastomotic strength was not significantly reduced at either time point and anastomotic hydroxyproline content was not significantly affected. We suggest that limited use of 5-FU during or immediately after operation does not necessarily affect early anastomotic healing in the intestine.
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Affiliation(s)
- J W de Waard
- Department of General Surgery, University Hospital, St Radboud, Nijmegen, The Netherlands
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Hendricks T, Martens MF, Huyben CM, Wobbes T. Inhibition of basal and TGF beta-induced fibroblast collagen synthesis by antineoplastic agents. Implications for wound healing. Br J Cancer 1993; 67:545-50. [PMID: 7679921 PMCID: PMC1968243 DOI: 10.1038/bjc.1993.100] [Citation(s) in RCA: 53] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Antineoplastic drugs, given in the perioperative period, are thought to be a hazard to wound repair. Since fibroblast collagen synthesis is crucial to healing, we examined the effects of bleomycin, cisplatin and 5-fluorouracil on collagen synthesis in confluent cultures of fibroblasts from human colon and skin. The drugs were added in final concentrations between 0.1 and 50 microM. Bleomycin did not affect collagen synthesis in colon fibroblasts but inhibited synthesis in skin fibroblasts. Collagen synthesis in colon fibroblasts was strongly, and specifically, inhibited by cisplatin while synthesis in skin fibroblasts was affected only slightly. 5-Fluorouracil had no effect whatsoever on the collagen synthetic capacity in either colon or skin fibroblasts. If skin fibroblasts were cultured in the presence of transforming growth factor beta (TGF beta), the antineoplastic agents inhibited the TGF beta-stimulated collagen synthesis at far lower concentrations than those needed to suppress non-stimulated synthesis. This effect was not observed in fibroblasts from colon. The possible implications of these observations, as pertain to the use of perioperative chemotherapy, are discussed. Since 5-fluorouracil did not directly affect collagen synthesis in colon fibroblasts under any of the conditions tested it is suggested that the data support the contention that this drug is relatively harmless for intestinal healing.
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Affiliation(s)
- T Hendricks
- Department of General Surgery, University Hospital Nijmegen, The Netherlands
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Martens MF, de Man BM, Hendriks T, Goris RJ. Collagen synthetic capacity throughout the uninjured and anastomosed intestinal wall. Am J Surg 1992; 164:354-60. [PMID: 1415943 DOI: 10.1016/s0002-9610(05)80904-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The capacity to synthesize collagen was measured throughout the intestinal tract of the rat, using an in vitro technique. In addition, the effect of anastomotic construction in either the ileum or the colon on collagen synthetic capacity at specific distant locations both 1 and 4 days after operation was investigated. Collagen synthetic capacity is relatively uniform throughout the large bowel. However, in the small bowel in which synthesis is lower than in the large bowel, synthesis is significantly higher in the most proximal and distal segments than in the intermediate tissue. Anastomotic construction in either part of the bowel strongly increases collagen synthetic capacity at the immediate wound site. The synthetic response is not restricted to the anastomotic site but appears to be more generalized and is, in the small bowel, to some extent specific for collagen since the collagen synthetic capacity is increased far more than the capacity to produce noncollagenous protein. Anastomotic construction in the colon has only minor, although sometimes significant, effects on collagen synthetic capacity in the ileum, and vice versa.
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Affiliation(s)
- M F Martens
- Department of General Surgery, Academic Hospital, University of Nijmegen, The Netherlands
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