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The effects of hyperthermic intraperitoneal chemoperfusion on colonic anastomosis: an experimental study in a rat model

The effects of hyperthermic intraperitoneal chemoperfusion on colonic anastomosis: an experimental study in a rat model

Tumori 2017; 103(3): 307 - 313

Article Type: ORIGINAL RESEARCH ARTICLE

DOI:10.5301/tj.5000610

Authors

Afag Aghayeva, Cigdem Benlice, Ismail Ahmet Bilgin, Pinar Atukeren, Gulen Dogusoy, Figen Demir, Deniz Atasoy, Bilgi Baca

Abstract

Introduction

Cytoreductive surgery (CRS) with subsequent hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising modality to treat and prevent peritoneal metastases. However, this treatment is associated with signficant morbidity and mortality. Whether or not CRS with HIPEC interferes with anastomotic healing has also been debated. This study was designed to investigate the effects of mitomycin C, cisplatin, oxaliplatin, and doxorubicin used in HIPEC treatment on colonic anastomosis healing in a rat model.

Methods

Sixty Wistar albino rats were employed in the study. Sigmoid resection and end-to-end colorectal anastomosis was performed in all rats. Group 1 rats underwent the surgical procedure alone, while group 2 rats were given hyperthermic intraperitoneal lavage with heated saline following surgery. Groups 3, 4, 5, and 6 had surgery with concomitant HIPEC treatment with mitomycin C, cisplatin, oxaliplatin, and doxorubicin, respectively. Anastomotic bursting pressures and hydroxyproline levels were evaluated.

Results

Regarding the hydroxyproline levels, groups 1 and 2 showed significantly higher values than other groups (p<0.001). However, there was no significant difference between the HIPEC treatment groups (groups 3, 4, 5, and 6) (p>0.05). When groups were compared regarding bursting pressure values, no significant differences were observed (p = 0.81).

Conclusions

This study demonstrated that the HIPEC procedure with mitomycin C, cisplatin, oxaliplatin and doxorubicin had negative effects on hydroxyproline levels, but had no detrimental effect on anastomotic bursting pressure in a rat model.

Article History

Disclosures

Financial support: Funding for this study was provided by Istanbul University Scientific Research Projects (number: 22359).
Conflict of interest: The authors have no conflicts of interest or financial ties to disclose.

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Introduction

The incidence of local recurrence and peritoneal metastasis (PM) in colon and rectal cancer patients is nearly 8% and 25%, respectively (1). Advances in treatment modalities for patients with PM from gastrointestinal or nongastrointestinal malignancies in order to improve survival rates have been on the uptrend for decades. The median survival time after manifestation of PM is about 6 months in colon cancer (2-3-4-5). An innovative strategy aimed at definitive disease eradication combines aggressive surgical cytoreduction with hyperthermic intraperitoneal chemotherapy (HIPEC) (6).

Cytoreductive surgery (CRS) combined with HIPEC appears effective in providing longer survival in the treatment of PM due to colorectal cancer (7-8-9). Besides, addition of HIPEC to CRS has been shown to increase survival compared with surgery alone (7, 9). Huang and colleagues (9) conducted a case-control study comparing the efficacy and safety of CRS alone versus CRS plus HIPEC in colorectal carcinoma with peritoneal carcinomatosis. The primary endpoint was overall survival (OS). They obtained a median OS of 13.7 months versus 8.5 months (p = 0.02) in favor of CRS plus HIPEC (9). In another study comparing long-term survival of patients with PM from colorectal carcinoma, Elias and colleagues (10) reported that patients who undergo CRS and HIPEC for resectable PM from colorectal carcinoma achieve a median survival of nearly 63 months compared to 24 months in patients only receiving modern chemotherapeutics (oxaliplatin and irinotecan). The 5-year survival rate for patients receiving CRS plus HIPEC in this study was 51% (10).

The morbidity rates for HIPEC range from 20% to 50% and the mortality rates range from 3% to 8% (5, 11). Regarding postoperative gastrointestinal complications after CRS plus HIPEC, the most common and clinically significant ones are anastomotic leak, small bowel perforation, pancreatitis, abscess, and bleeding (12-13-14-15-16). Anastomotic leak after colon and rectal surgery is associated with high mortality and morbidity and leads to increased healthcare costs (12-13-14-15-16-17-18).

The aim of this experimental study was to investigate the effects of mitomycin C, cisplatin, oxaliplatin, and doxorubicin used in the HIPEC procedure on colonic anastomoses in a rat model. To design such a study on human patients would have taken a larger sample size and long duration of follow-up, and would have raised ethical concerns. Since rat models for evaluation of bursting pressure are extensively described in the literature, we elected to use a rat model in the present study.

Material and methods

This study was performed after approval (approval code number: 2012/50) from the Ethics Committee of Istanbul University, Istanbul, Turkey, and was conducted according to the Turkish Act for Care and Use of Experimental Animals (2011) No. 28141. A total of 60 adult male Wistar albino rats weighing 250-300 g were obtained from the Istanbul University Experimental Animal Production and Research Laboratory. The rats were kept in standard colony cages (15 × 25 × 40 cm; 4 rats/cage) under controlled conditions with a temperature of 18-23°C, a ratio of 10 hours of light to 14 hours of darkness, and 50% to 55% humidity. The animals were fed a standard laboratory diet and tap water ad libitum 6 hours after surgery. Rats were divided into 6 groups. Groups were designed as shown in Table I.

Study groups

Group Surgical procedure
C = cisplatin; D = doxorubicin; HIPEC = hyperthermic intraperitoneal chemotherapy; HIPEL = hyperthermic intraperitoneal lavage; M = mitomycin C; O = oxaliplatin.
* Chemoperfusion performed at 42˚C for 90 minutes.
† Chemoperfusion performed at 42˚C for 60 minutes.
1 Sigmoid resection and colorectal anastomosis
2 Sigmoid resection, colorectal anastomosis and HIPEL with saline*
3 Sigmoid resection, colorectal anastomosis and HIPEC with M 2 mg/kg*
4 Sigmoid resection, colorectal anastomosis and HIPEC with C 5 mg/kg*
5 Sigmoid resection, colorectal anastomosis and HIPEC with O 25 mg/kg†
6 Sigmoid resection, colorectal anastomosis and HIPEC with D 2 mg/kg*

Surgical procedure

Surgery was performed through a 3-cm midline incision under intraperitoneal ketamine 50 mg/kg (Ketalar; Parke-Davis, Turkey) and xylazine 5 mg/kg (Rompun; Bayer AG, Germany). Before administration of the intraperitoneal chemotherapy, each rat underwent a sigmoid colon resection with end-to-end colorectal anastomosis. Anastomoses were completed with interrupted 6-0 polypropylene sutures (Prolene, Ethicon, USA). During HIPEC application, an inflow catheter was placed between the liver and the diaphragm, and an outflow catheter was placed in the pelvis. A temperature probe was placed in the abdomen (Fig. 1). Additionally, a piece of small sponge was spread over the bowel to prevent catheter occlusion by the mesentery. During intraperitoneal perfusion, the position of the sponge was changed every 15 minutes to obtain homogeneous lavage. The abdomen was left open.

Localization of inflow cannula, outflow cannula, and heat probe.

Hyperthermic intraperitoneal perfusion procedure

Perfusion was performed with an open technique, using a hyperthermia pump (Belmont, USA). The peritoneal perfusate, consisting of 300 mL NaCl (0.9%), was warmed to 42°C and infused into the abdomen at 30-40 mL/min for 60 minutes for the saline (group 1) and oxaliplatin groups (group 5), and for 90 minutes for the mitomycin C, cisplatin, and doxorubicin groups. Chemotherapeutic agents were dissolved in NaCl (0.9%) and added to the perfusate after the perfusion fluid had reached 42°C (about 5 minutes). When the chemoperfusion procedure was finished, all catheters and the temperature probe were removed and the midline incision was closed in 2 layers with 3-0 polypropylene sutures. To prevent dehydration 10 mL NaCl was injected subcutaneously.

After completion of the combined procedure of sigmoid resection ± peritoneal perfusion, each animal was fed standard chow with no restrictions. The animals were killed on postoperative day 4 with an overdose of anesthetic.

Measurement of bursting pressure

The bursting pressure was measured while preserving the anastomotic segment untouched in situ. The distal part of the anastomosis was ligated just above the peritoneal reflection of the rectum and the abdomen was filled with isotonic saline. The colon segment was transected at a distance of 5 cm proximal to the anastomosis. The cannula of a perfusator was inserted into the proximal bowel end. The cannula was encircled and tied with 3-0 silk to avoid air leakage and was connected to an infusion pump. A stopcock was placed between the cannula and sphygmomanometer. The colon was insufflated with air at a constant rate of 6 mL/min. The bursting pressure value was noted when the first air bubbles were seen. Localization of the rupture site on the anastomosis was observed for all subjects. After recording of the bursting pressure, the anastomotic segment was divided into 2 equal parts: one was placed in 4% formalin solution for histopathological assessment and the other was stored at -70°C for hydroxyproline measurement. The microscopic appearance of one sample from each group is shown in Figure 2.

Microscopic appearance of sigmoid resection and anastomosis (A), HIPEL (B), HIPEC with mitomycin C (C), HIPEC with cisplatin (D), HIPEC with oxaliplatin (E), and HIPEC with doxorubicin (F). H&E, ×200. HIPEC = hyperthermic intraperitoneal chemotherapy; HIPEL = hyperthermic intraperitoneal lavage.

Hydroxyproline determination

The colon segment including the anastomosis was weighed and homogenized in physiological saline solution (1/10, w/v) using a tissue grinder fitted with a Teflon pestle (RZR 2021, Heidolph, Germany). Homogenates were centrifuged at 1,500 rpm for 15 minutes and the resulting supernatants were hydrolyzed by adding hydrochloric acid (37%) and incubated at ~100°C for 16-18 hours. The amino acid was oxidized forming a pyrrole derivative, which was colored with Ehrlich’s reagent and quantitatively determined spectrophotometrically at 560 nm using the hydroxyproline kit (Hypronosticon, Organon, Netherlands). Results were interpreted as µg/mg wet tissue.

Histopathological examination

The colon segments that were fixed in 4% formalin solution were embedded in paraffin wax. Five-micron-thick sections were stained with hematoxylin-eosin and examined under a light microscope by a pathologist. The evaluated parameters of wound healing included granulation tissue formation, muscular tissue improvement, re-epithelialization, fibroblast proliferation, collagen deposition, and mononuclear cell infiltration.

Statistical analysis

Statistical analysis was performed using SPSS version 16.0 (SPSS, USA). In order to determine whether the continuous variables (bursting pressure and hydroxyproline level) were normally distributed the Shapiro-Wilk test was utilized. Descriptive statistics were presented as mean ± standard deviation for hydroxyproline levels, and median (range) for bursting pressure values. To compare bursting pressure values and hydroxyproline levels among the study groups the Kruskal-Wallis test was used. The origin of the difference was calculated with Dunn’s method. A p value less than 0.05 was considered statistically significant.

Results

We employed 60 rats in an attempt to investigate the possible detrimental effects of HIPEC on colonic anastomosis. Treatment with chemotherapeutic agents was performed using clinically available agents such as mitomycin C, cisplatin, oxaliplatin, and doxorubicin. In particular, we assessed the bursting pressures and hydroxyproline levels of the anastomoses.

Six rats died during the study period, thus anastomoses were assessed in 54 rats. One rat each from groups 1, 2 and 6, and two rats from group 4 were lost due to intestinal obstruction. The cause of death for one rat from group 3 was not found.

Bursting on the anastomotic line occurred in all subjects. The bursting pressure values and hydroxyproline levels of the groups are shown in Table II. Regarding normality, both bursting pressure values and hydroxyproline levels were nonnormally distributed according to the Shapiro-Wilk test. For comparison of the hydroxyproline levels, the Kruskal-Wallis test was utilized and the difference was found to be statistically significant (p<0.001). After pairwise multiple comparisons using Dunn’s method, it was observed that the origin of the difference was in groups 1 and 2, which showed significantly higher values of hydroxyproline. Conversely, differences in hydroxyproline levels among the groups treated with HIPEC were not significant.

Bursting pressure values and hydroxyproline levels of the groups

Group 1 (SR + CA) Group 2 (SR + CA + S) Group 3 (SR + CA + M) Group 4 (SR + CA + C) Group 5 (SR + CA + O) Group 6 (SR+CA+D) P value
C = cisplatin; CA = colorectal anastomosis; D = doxorubicin; M = mitomycin C; O = oxaliplatin; S = saline; SR = sigmoid resection.
* Kruskal-Wallis test.
** Kruskal-Wallis test and Dunn’s method.
Bursting pressure (mmHg) Median (range) 70 (60-80) 70 (60-85) 60 (50-90) 80 (62.5-95) 70 (60-92.5) 80 (65-80) p = 0.81*
Hydroxyproline level (µg/mg wet tissue) (Mean ± SD) 1.55 ± 0.25 1.17 ± 0.21 0.84 ± 0.06 0.70 ± 0.04 0.74 ± 0.04 0.82 ± 0.05 p<0.001**

For comparison of the bursting pressure values the Kruskal-Wallis test was performed, and there was no significant difference among groups (p = 0.81).

The histopathological examination characteristics of the groups are shown in Table III. The values are presented as semiquantitative average values.

Histopathological characteristics of the groups

Group 1 (SR + CA) Group 2 (SR + CA + S) Group 3 (SR + CA + M) Group 4 (SR + CA + C) Group 5 (SR + CA + O) Group 6 (SR + CA + D)
C = cisplatin; CA = colorectal anastomosis; D = doxorubicin; M = mitomycin C; O = oxaliplatin; S = saline; SR = sigmoid resection.
The values of histopathological parameters were scored as:
* mild (+), moderate (++), severe (+++)
† negative (-), mild (+), moderate (++), complete (+++)
§ negative (-), mild single layer of cuboidal epithelium (+), multiple single rows (++), almost a full single layer of cuboidal epithelium (+++), complete single layer of cuboidal epithelium (++++), single layer of glandular epithelium (+++++), normal glandular mucosa (++++++).
Granulation tissue formation* + ++ ++ ++ ++ ++
Muscular tissue improvement† ++/+++ ++ ++ ++ ++ ++
Re-epithelialization§ ++ ++ ++ ++/+++ ++ ++
Fibroblast proliferation* +++ + + + + +
Collagen deposition* +++ ++ ++ + + +
Mononuclear cell infiltration* ++ ++ ++ +++ +++ ++

Discussion

This study showed that administration of mitomycin C, cisplatin, oxaliplatin, and doxorubicin in hyperthermic conditions did not worsen anastomotic bursting pressure, but did have an adverse effect on anastomotic hydroxyproline levels after colorectal surgery in a rat model. To the best of our knowledge, this is the first experimental study investigating the effects of 4 different intraperitoneal chemotherapeutic agents on colonic anastomosis.

The incidence of anastomotic leak after colorectal cancer surgery ranges from 2.6% to 19.0% (19-20-21-22-23-24). Anastomotic leak after colorectal surgery increases postoperative morbidity, mortality, length of hospital stay, and nosocomial infection rates, and decreases quality of life (18, 25, 26). Moreover, anastomotic leak after colorectal cancer surgery may result in poor functional and oncological outcomes (27). Postoperative mortality associated with anastomotic complications in colorectal surgery has been reported to range from 6% to 22% (28-29-30-31). Several factors, including surgical technique, intestinal integrity, tension on the anastomosis, tissue blood flow, oxygenation, and drug- and patient-related factors predisposing to poor healing are associated with anastomotic leak (32, 33).

In the present study, we showed that the studied chemotherapeutic agents have a negative effect on hydroxyproline levels, while no negative effect on bursting pressure values was observed. The hydroxyproline levels were significantly higher in the sigmoid resection with colorectal anastomosis alone group (group 1) and the sigmoid resection plus colorectal anastomosis with hyperthermic intraperitoneal lavage group (group 2) than in groups in which chemotherapeutic agents were used. In line with our study, other studies also demonstrated that intraperitoneal administration of oxaliplatin, 5-FU, mitomycin C, and cisplatin impair the healing of colonic anastomoses in rats (5, 34-35-36-37). Collagen is an important molecule in all phases of wound healing and is critical for the restoration of tissue integrity and strength. Changes in hydroxyproline content reflect changes in the amount of collagen (38, 39).

Bursting pressure is regarded as an accurate method for evaluation of anastomotic healing in the early period (40, 41). The discordance between the hydroxyproline and bursting pressure results in this study could be attributed to the amount of collagen tissue. As a single parameter, hydroxyproline levels can sometimes provide inaccurate results. This is due to the fact that hydroxyproline levels depend on the quantity of collagen fibrils rather than the quality of collagen. In addition to the mass of collagen, the quality of the collagen fibrils is also important for the strength of the anastomosis. Therefore, sometimes collagen quantity and quality and mechanical parameters of the anastomosis are not correlated (40, 42).

Evaluation of intestinal anastomotic healing is based on the assessment of mechanical, biochemical, and histopathological parameters (33, 43). The best-known mechanical measurement methods are bursting pressure, bursting wall tension, and tensile strength measurements. Unfortunately, none of these methods is ideal. The bursting technique alone evenly distributes transmural pressure and is, for that reason, considered the testing method that more closely approximates the clinical situation (5). Although some studies have concluded that intraperitoneal mitomycin C and cisplatin decrease the bursting pressure of colonic anastomosis in rats, in the present study HIPEC treatment with these agents did not decrease the bursting pressures (5, 36).

One of the major benefits of HIPEC is the exposure of cancerous tissue to high drug concentrations for a period of time, while at the same time reducing the systemic effects of the drugs. The efficacy of intraperitoneal chemotherapy increases with hyperthermia, since hyperthermia enhances cytotoxicity and improves drug penetration to the tissues (44). In this study, hyperthermic conditions alone (group 2) did not decrease the anastomotic bursting pressure values.

There is no standardized protocol for the duration of perfusion of chemotherapeutic drugs during HIPEC. The duration ranges from 30 to 120 minutes (45) and different institutions use different protocols. In our clinic, we use the Sugarbaker protocol (44). In this protocol oxaliplatin is given for 60 minutes, while mitomycin C, cisplatin, and doxorubicin are given for 90 minutes during the HIPEC procedure. The drugs are given at lower doses for a prolonged period compared with other protocols that give higher doses in a shorter time. It was hypothesized that this approach would achieve higher drug concentrations in the target cells.

The wound healing process includes 4 distinct but overlapping phases of hemostasis, inflammation, proliferation, and remodeling (46). Further comparisons of the anastomoses regarding the histopathological features including granulation tissue formation, muscular tissue improvement, re-epithelialization, fibroblast proliferation, collagen deposition, and mononuclear cell infiltration could give further information about anastomotic healing at the cellular level.

The fact that we evaluated the anastomoses in healthy rats is a possible limitation of this study. Studies conducted in animals with colon tumor models may give additional results.

According to the results of this study, it could be suggested that a selected group of colorectal cancer patients who are candidates for the HIPEC procedure could be protected from diverting stoma construction since the effect of HIPEC was not found to be as detrimental as was thought previously. The advantage of this would be avoidance of a second operation (stoma closure), better quality of life, lesser burden on finance, and no need for a stoma therapist or nurse. In the long term this would lead to lower morbidity and lesser cost. However, further studies are needed before any conclusive statements can be made.

Conclusions

In conclusion, our results indicated that the administration of intraperitoneal mitomycin C, doxorubicin, cisplatin, and oxaliplatin in hyperthermic conditions did not decrease the anastomotic bursting pressure. Our observations support the importance of preclinical studies in appropriate experimental models to optimize the use of chemotherapy, which widely contributes to the cure of cancer, in spite of the advent of targeted agents (47).

Disclosures

Financial support: Funding for this study was provided by Istanbul University Scientific Research Projects (number: 22359).
Conflict of interest: The authors have no conflicts of interest or financial ties to disclose.
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Authors

Affiliations

  • Department of General Surgery, Acibadem University, School of Medicine, Istanbul - Turkey
  • Istanbul University, Cerrahpasa Medical School, Istanbul - Turkey
  • Department of Biochemistry, Istanbul University, Cerrahpasa School of Medicine, Istanbul - Turkey
  • Department of Pathology, Gayrettepe Florence Nightingale Hospital, Istanbul - Turkey
  • Department of Public Health, Acibadem University, School of Medicine, Istanbul - Turkey

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