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Comparative analysis of the incidence of surgical site infections in patients with liver resection for colorectal hepatic metastases after neoadjuvant chemotherapy

Published:November 25, 2013DOI:https://doi.org/10.1016/j.jss.2013.11.1092

      Abstract

      Background

      The aim of this study was to identify the incidence of surgical site infections (SSIs) and postoperative complications, as defined by the Clavien–Dindo classification, after hepatic resection for metastatic colorectal cancer in patients with and without associated neoadjuvant chemotherapy.

      Methods

      A total of 181 patients were studied retrospectively. Patients were divided into two groups: the first group comprised patients with associated neoadjuvant chemotherapeutic treatment for liver metastases with a latency time <8 wk and the second group comprised patients without associated neoadjuvant chemotherapy.

      Results

      Variables of duration of liver surgery, length of total hospital stay, and length of postoperative hospital stay seem to be correlated with SSIs and postoperative complications, P < 0.005 and P < 0.0001, respectively. Duration of surgery is a risk factor for SSIs, with an odds ratio of 1.15, and for complications according to the Clavien–Dindo classification, with an odds ratio of 1.35.

      Conclusions

      Neoadjuvant chemotherapy was not a significant risk factor for SSIs, whereas the total length of hospital stay, length of postoperative hospital stay, and duration of surgery were independent predictors of SSIs and complications according to the Clavien–Dindo classification.

      Keywords

      1. Introduction

      Postoperative infections are frequent complications and have a significant impact on the length of hospital stay, morbidity, and mortality [
      • Garwood R.A.
      • Sawyer R.G.
      • Thompson L.
      • Adams R.B.
      Infectious complications after hepatic resection.
      ]. Surgical site infections (SSIs) are the most common hospital-acquired infections among surgical patients, with a significant impact on both patient morbidity and health care costs according to the U.S. Centers for Disease Control and Prevention through the National Nosocomial Infections Surveillance program [
      • Reilly J.
      • Allardice G.
      • Bruce J.
      • Hill R.
      • McCoubrey J.
      Procedure-specific surgical site infection rates and postdischarge surveillance in Scotland.
      ].
      An SSI is defined as an infection either with incisional involvement of the skin alone or with the involvement of deep tissues or organs. The criteria for defining SSIs are as follows: superficial incisional SSI if only the skin and subcutaneous tissue are involved; deep incisional SSI with the involvement of deep soft tissues, such as fascia and muscles; and organ-space SSI when the organ or space is involved [
      • Malone D.L.
      • Genuit T.
      • Tracy J.K.
      • et al.
      Surgical site infections: reanalysis of risk factors.
      ]. In recent years, a decreasing incidence of perioperative septic complications has been reported, the result of advances in surgical techniques, new suturing materials, better perioperative management, and the implementation of infection surveillance [
      • Uchiyama K.
      • Ueno M.
      • Ozawa S.
      • et al.
      Risk factors for postoperative infectious complications after hepatectomy.
      ]. Neoadjuvant chemotherapy for colorectal cancer seems to enhance the risk of surgical complications and infections [
      • Garwood R.A.
      • Sawyer R.G.
      • Thompson L.
      • Adams R.B.
      Infectious complications after hepatic resection.
      ], suppressing the hematopoietic system, and causing neutropenia. It is also associated with the risk of life-threatening infections [
      • Crawford J.
      • Dale D.C.
      • Lyman G.H.
      Chemotherapy-induced neutropenia: risks, consequences, and new directions for its management.
      ].
      The aim of this study was to identify the incidence of SSIs and postoperative complications according to the Clavien–Dindo classification, (Table 1) [
      • Dindo D.
      • Demartines N.
      • Clavien P.A.
      Classification of surgical complications a new proposal with evaluation in a cohort of 6336 patients and results of a survey.
      ], after hepatic resection for metastatic colorectal cancer in patients with and without associated neoadjuvant chemotherapy. The latter are increasingly being used to enlarge the cohort of patients who can be offered hepatic resection for malignancy.
      Table 1Clavien–Dindo classification of postoperative surgical complications.
      GradesDefinitions
      IAny deviation from the normal postoperative course without the need of pharmacologic treatment or surgical, endoscopic, and radiologic interventions. Allowed therapeutic regimens are drugs as antiemetic, antipyretics, analgesics, diuretics, electrolytes, and physiotherapy. This grade also includes the wound infections opened at the bedside
      IIRequiring pharmacologic treatment with drugs other than such allowed for grade I complications: blood transfusions and parenteral nutrition are also included
      IIIRequiring surgical, endoscopic, and radiologic interventions:

      a. Intervention not under general anesthesia

      b. Intervention under general anesthesia
      IVLife-threatening complication (including CNS complications)
      Brain hemorrhage, ischemic stroke, subarachnoid bleeding, but excluding transient ischemic stroke.
      requiring IC-ICU management:

      a. Single organ dysfunction (including dialysis)

      b. Multiorgan dysfunction
      VDeath of the patient
      CNS = central venous system; IC = intermediate care; ICU = intensive care unit.
      Brain hemorrhage, ischemic stroke, subarachnoid bleeding, but excluding transient ischemic stroke.
      Modern management of colorectal liver metastases is multimodal and incorporates open and laparoscopic surgery, ablative therapies such as radio frequency ablation or microwave ablation, and (neo)adjuvant chemotherapy. Most patients with hepatic metastases should be considered for resectional surgery if all the tumor(s) can be resected, as this offers the only opportunity for prolonged survival.
      However, the real impact of these agents on clinical outcomes after hepatic resection remains unclear.

      2. Materials and methods

      A total of 181 patients who had undergone hepatic surgery for metastatic colorectal cancer in three surgical units, the Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), Palermo, Italy, Azienda Ospedaliero-Universitaria Policlinico-Vittorio Emanuele, and Humanitas Centro Catanese di Oncologia, Catania, Italy, between January 2006 and December 2011 were investigated retrospectively. Data were collected on patient age, gender, comorbidities, site of primary tumor, type of hepatic resection, duration of surgery, and the total length of hospital stay and the length of postoperative stay and are reported in Table 2. Patients were divided into two groups: the first group comprised patients who had undergone hepatic resection for metastatic colorectal cancer after a latency time <8 wk since the end of the neoadjuvant chemotherapy and the second group comprised patients who had undergone hepatic resection without associated neoadjuvant chemotherapy [
      • Hasegawa K.
      • Takahashi M.
      • Ohba M.
      • et al.
      Perioperative chemotherapy and liver resection for hepatic metastases of colorectal cancer.
      ]. The two groups differed in the volume of type of resection. Patients with significant progression of metastatic disease and-or the development of new lesions during neoadjuvant chemotherapy were not included in this series.
      Table 2General characteristics of patients who underwent hepatic resection for metastatic colorectal cancer.
      No. of patients181
      Median age (y) ± standard deviation63 ± 10 y
      Gender, n (%)
       Male103 (56.9%)
       Female78 (43.1%)
      Location of primary tumor, n (%)
       Right colon41 (22.7%)
       Transverse colon4 (2.2%)
       Left colon29 (16%)
       Sigmoid colon66 (36.5%)
       Rectosigmoid joint2 (1.1%)
       Transverse + sigmoid colon1 (0.5%)
       Rectum37 (20.5%)
       Anus1 (0.5%)
      Associated risk factors, n (%)
       Diabetes21 (11.6%)
       Obesity11 (6%)
       Smoking28 (15.4%)
       Respiratory problems14 (7.7%)
       Cardiovascular disease70 (38.6%)
       Renal failure3 (1.6%)
       Liver disease10 (5.5%)
      Major liver resection, n (%)83 (45.8%)
       Left hepatectomy24 (29%)
       Right hepatectomy48 (57.8%)
       Left lobectomy11 (13.2%)
      Minor liver resection, n (%)98 (54.2%)
       Wedge resection81 (82.6%)
       Bisegmentectomy13 (13.4%)
       Right sectorectomy4 (4%)
      Duration of liver surgery (min): mean ± SD404 ± 154
      Length of total hospital stay (d): mean ± SD10 ± 6
      Length of postoperative hospital stay (d): mean ± SD9 ± 7
      Neoadjuvant chemotherapy, n (%)52 (28.7%)
      No chemotherapy, n (%)129 (71.2%)
      In the first group, patients were assigned to six cycles of FOLFOX4 (Folinic acid, Fluorouracil, Oxaliplatin) before surgery; each cycle of chemotherapy lasted 14 d, with the subsequent cycle set to start on day 15, as previously described by Nordlinger et al. [
      • Sorbye H.
      • Mauer M.
      • Gruenberger T.
      • et al.
      Predictive factors for the benefit of perioperative FOLFOX for resectable liver metastases in colorectal cancer patients (EORTC Intergroup Trial 40983).
      ,
      • Nordlinger B.
      • Sorbye H.
      • Glimelius B.
      • et al.
      Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial.
      ]. The incidence of SSIs classified as superficial, deep incisional, and organ/space, and all other infectious complications were evaluated in the two groups. We also used the Clavien–Dindo classification for postoperative complications.
      A comparison of means for quantitative variables was done using the Student t-test at a P = 0.05 significance level using Analyse-it for Microsoft Excel (version 3.0; Analyse-it Software, Ltd, http://www.analyse-it.com/; Leeds, United Kingdom 2012). Univariate contingency table analysis was done using χ2 tests at the P = 0.05 significance level also using Analyse-it for Excel.
      Multivariate logistic analysis was done with Epi Info (version 3.5.4, 2012; Centers for Disease Control and Prevention, Atlanta, GA). Regression factors were both quantitative (age and the length of intervention) and qualitative dichotomous (presence-absence). Risk was expressed as an odds ratio (OR) approximating the relative risk of having the outcome given the factor with 95% confidence limits.

      3. Results

      This study enrolled 181 patients with a median age of 63 ± 10 y. There were 103 males (56.9%) and 78 females (43.1%) as shown in Table 2.
      The first group (Table 3) included 129 patients without associated chemotherapeutic treatment. The median age was 63 ± 9 y with 74 males (57%) and 55 females (43%). Duration of surgery was estimated at 408 ± 158 min, and all patients underwent an initial time of adhesiolysis, which lengthened the intervention. The total length of hospital stay and length of postoperative hospital stay were 10 ± 6 and 9 ± 8 d, respectively.
      Table 3General characteristics of patients who underwent hepatic resection for metastatic colorectal cancer with and without associated chemotherapy treatment.
      VariablesNo chemotherapyNeoadjuvant chemotherapyStudent's t-test
      No. of patients12952
      Mean age (y) ± SD63 ± 964 ± 13
       Male74 (57%)29 (56%)N.S. χ2 test
       Female55 (43%)23 (44%)N.S. χ2 test
      Location of primary tumor, n (%)N.S. χ2 test
       Right colon30 (23.2%)11 (21.2%)
       Transverse colon3 (2.4%)1 (1.9%)
       Left colon21 (16.3%)8 (15.4%)
       Sigmoid colon49 (38%)17 (32.7%)
       Rectosigmoid joint2 (1.4%)1 (1.9%)
       Transverse + sigmoid colon0 (0%)1 (1.9%)
       Rectum24 (18.7%)13 (25%)
      Associated risk factors, n (%)N.S. χ2 test
       Diabetes13 (10%)8 (15.4%)
       Obesity7 (5.4%)4 (7.7%)
       Smoking20 (15.5%)8 (15.4%)
       Respiratory problems8 (62%)6 (11.6%)
       Cardiovascular disease39 (30.2%)20 (38.4%)
       Renal failure3 (2.3%)0 (0%)
       Liver disease6 (4.6%)4 (7.7%)
      Major liver resection, n (%)56 (43.4%)27 (51.9%)N.S. χ2 test
       Left hepatectomy8 (14.2%)16 (59.2%)
       Right hepatectomy42 (75%)6 (22.2%)
       Left lobectomy6 (10.8%)5 (18.6%)
      Minor liver resection, n (%)73 (56.6%)25 (48.1%)N.S. χ2 test
       Wedge resection63 (86.3%)18 (72%)
       Bisegmentectomy8 (11%)5 (20%)
       Right sectorectomy2 (2.7%)2 (8%)
      Duration of liver surgery (min): mean ± SD408 ± 158396 ± 145N.S. Student t-test
      Length of total hospital stay (d): mean ± SD10 ± 69 ± 5N.S. Student t-test
      Length of postoperative hospital stay (d): mean ± SD9 ± 88 ± 4N.S. Student t-test
      N.S. = nonsignificant.
      The location of the primary tumor was the sigmoid colon in 49 patients (38%), the right colon in 30 (23.2%), the rectum in 24 (18.7%), the left colon in 21 (16.3%), the transverse colon in 3 (1.9%), and the rectosigmoid joint in 2 (1.4%). Major liver resection was performed in 56 patients (43.4%), with 8 (14.2%) left hepatectomies, 42 (75%) right hepatectomies, and 6 (10.8%) left lobectomies. Minor liver resection was performed in 73 patients (56.6%) with 63 (86.3%) wedge resections, 8 (11%) bisegmentectomies, and 2 (2.7%) right sectorectomies.
      Forty-one patients (31.7%) experienced SSIs as defined by the SSI classification with 7 (17%) superficial incisional, 17 (41.5%) deep incisional, and 17 (41.5%) organ/space infections, with the last infection leading to an increase in the total hospital stay. In the remaining 88 patients (68.3%) there were no SSIs.
      In 61 patients (47.29) there were postoperative complications, which we defined according to the Clavien–Dindo classification: grade I in 14 patients (23%), grade II in 23 (37.7%), grade IIIa in 16 (26.2%), grade IIIb in 4 (6.5%), grade IVa in 3 (5%), and grade V in 1 patient (1.6%). There were no postoperative complications in the remaining 68 patients (52.8%).
      The second group (Table 4) consisted of 52 patients who had undergone neoadjuvant chemotherapy. The median age was 64 ± 13 y with 29 males (56%) and 23 females (44%). The duration of surgery was estimated at 396 ± 145 min, and all patients underwent an initial time of adhesiolysis, which lengthened the intervention. The total length of hospital stay and length of postoperative hospital stay were 9 ± 5 and 8 ± 4 d, respectively.
      Table 4Postoperative complications according to the SSI and Clavien–Dindo classification.
      VariablesNo chemotherapyNeoadjuvant chemotherapyTest
      Chi-squared tests between proportions of chemotherapy and occurrence of SSI or complications according to the Clavien–Dindo classification yielded nonsignificant results.
      Number of patients12952
      SSI, n (%)41 (31.8%)16 (30.8%)N.S.
       Superficial incisional SSI7 (17%)5 (31.3%)
       Deep incisional SSI17 (41.5%)7 (43.7%)
       Organ/space SSI17 (41.5%)4 (25%)
      Number of SSIs, n (%)88 (68.2%)36 (69.2%)
      Clavien–Dindo surgical complications, n (%)61 (47.3%)19 (36.5%)N.S.
       I14 (23%)4 (21%)
       II23 (37.7%)9 (47.4%)
       IIIa16 (26.2%)4 (21%)
       IIIb4 (6.5%)1 (5.3%)
       IVa3 (5%)1 (5.3%)
       IVb
       V1 (1.6%)
      No Clavien–Dindo surgical complications, n (%)68 (52.7%)33 (63.5%)
      Chi-squared tests between proportions of chemotherapy and occurrence of SSI or complications according to the Clavien–Dindo classification yielded nonsignificant results.
      The location of the primary tumor was the sigmoid colon in 17 patients (32.7%), the rectum in 13 (25%), the left colon in 8 (15.4%), the right colon in 11 (21.2%), the transverse colon in 1 (1.9%), the rectosigmoid joint in 1 (1.9%), and the transverse and sigmoid colon in 1 (1.9%). Major liver resection was performed in 27 patients (51.9%) with 16 (59.2%) left hepatectomies, 6 (22.2%) right hepatectomies, and 5 (18.6%) left lobectomies. Minor liver resection was performed in 25 patients (48.1%) with 18 (72%) wedge resections, 5 (20%) bisegmentectomies, and 2 (8%) right sectorectomies.
      Sixteen patients (30.7%) experienced SSI as defined by the SSI classification, with 5 (31.3%) superficial incisional, 7 (43.7%) deep incisional, and 4 (25%) organ/space infections, the last infection led to an increase in total hospital stay. There were no SSIs in the other 36 patients (69.3%).
      In 19 patients (36.5%) there were postoperative complications as defined by the Clavien–Dindo classification: grade I in four patients (21%), grade II in nine (47.4%), IIIa in four (21%), IIIb in one (5.3%), and IVa in one patient (5.3%). There were no postoperative complications in the other 33 patients (63.5%).
      There were no statistically significant preoperative patient characteristics shared by the two groups. Statistical analyses of two-by-two contingency tables of exposure (to chemotherapy) versus outcome (SSI or complications according to the Clavien–Dindo classification) showed no significant differences in the proportion of cases according to the presence of chemotherapy (Table 4).
      Statistical analyses of two-by-two contingency tables of various preoperative and intraoperative characteristics versus outcome (SSI or complications according to the Clavien–Dindo classification) showed no significant differences in the proportion of cases related to the presence of chemotherapy (Table 5). The duration of surgical intervention was found to have been significantly higher in patients who then developed SSIs or complications according to the Clavien–Dindo classification (Table 5). None of the operations were performed with a mini-invasive approach.
      Table 5Preoperative and intraoperative characteristics of patients who developed SSI or complications according to the Clavien–Dindo classification.
      VariablesSSINo SSITest (significance)
      Number of patients57124
      Gender, n (%)
       Male37 (64.9%)66 (53.2%)N.S.
       Female20 (35.1%)58 (46.8%)
      Associated risk factors, n (%)
       Diabetes4 (7.0%)17 (13.7%)N.S.
       Obesity2 (3.5%)9 (7.3%)N.S.
       Smoking9 (15.8%)19 (15.3%)N.S.
       Respiratory problems3 (5.3%)11 (8.9%)N.S.
       Cardiovascular disease5 (8.8%)8 (6.5%)N.S.
       Renal failure1 (1.8%)2 (1.6%)N.S.
       Liver disease4 (7%)6 (4.8%)N.S.
      Major liver resection, n (%)26 (45.6%)57 (46.0%)N.S.
      Duration of liver surgery (min): mean ± SD444 ± 153386 ± 151P < 0.02
      Length of total hospital stay (d): mean ± SD13.2 ± 88.5 ± 3.4P < 0.0001
      Length of postoperative hospital stay (d): mean ± SD12.2 ± 10.37.2 ± 3P < 0.0001
      ComplicationNo complication
      Gender, n (%)
       Male51 (63.8%)52 (51.5%)N.S.
       Female29 (36.3%)49 (48.5%)
      Associated risk factors, n (%)
       Diabetes7 (8.8%)14 (13.9%)N.S.
       Obesity4 (5%)7 (6.9%)N.S.
       Smoking16 (20%)12 (11.9%)N.S.
       Respiratory problems6 (7.5%)8 (7.9%)N.S.
       Cardiovascular disease7 (8.8%)6 (5.9%)N.S.
       Renal failure1 (1.3%)2 (2%)N.S.
       Liver disease4 (5%)6 (5.9%)N.S.
      Major liver resection, n (%)31 (38.8%)52 (51.5%)N.S.
      Duration of liver surgery (min): mean ± SD460 ± 154360 ± 139P < 0.0001
      Length of total hospital stay (d): mean ± SD12.4 ± 78 ± 4P < 0.0001
      Length of postoperative hospital stay (d): mean ± SD11 ± 97 ± 3P < 0.0001
      The total length of hospital stay and the length of postoperative stay were significantly higher in patients who later developed complications.
      Despite the small number of patients, the two study groups were comparable. To better evaluate the available data and to partly overcome the constraints because of the limited number of cases, a multiple logistic regression analysis was used to explore the independent risk of complications (SSI or complications according to the Clavien–Dindo classification) because of preoperative and intraoperative (length of surgery) factors. Preoperative factors considered were gender and age, the presence of neoadjuvant chemotherapy, and associated risk factors (diabetes, smoking, respiratory, and cardiovascular problems). For both SSIs and complications according to the Clavien–Dindo classification, a reduced model was also used, removing factors with a P value farther from the chosen significance level.
      In neither case did the reduced model show a significant worsening of goodness-of-fit, and the regression was at least marginally (borderline) statistically significant, as indicated in Table 6.
      Table 6Multivariate OR for significant independent predictors of SSI and complications according to the Clavien–Dindo classification.
      VariablesOR (95% Cl)P value
      SSI
      Likelihood ratio test for goodness-of-fit = 9.42 (5 df), P = 0.093 borderline significant.
       Duration of liver surgery (h)1.15 (1.01–1.31)0.03
       Gender0.69 (0.35–1.35)0.28
       Diabetes0.59 (0.18–1.94)0.39
       Respiratory problems0.53 (0.13–2.09)0.36
       Cardiovascular disease1.78 (0.50–6.23)0.36
      Clavien–Dindo complications
      Likelihood ratio test for goodness-of-fit = 25.3 (5 df), P = 0.0001.
       Neoadjuvant chemotherapy0.61 (0.30–1.26)0.18
       Duration of liver surgery (h)1.32 (1.151.51)0.0001
       Gender0.68 (0.36–1.30)0.25
       Smoking1.55 (0.64–3.78)0.33
       Cardiovascular disease2.20 (0.60–8.11)0.23
      Number of cases: 181. In boldface are given the factors exceeding the significance level of P < 0.05.
      Likelihood ratio test for goodness-of-fit = 9.42 (5 df), P = 0.093 borderline significant.
      Likelihood ratio test for goodness-of-fit = 25.3 (5 df), P = 0.0001.
      For both the SSI and the complication outcomes, logistic regression analysis (Table 6) indicated that after adjusting the demographics and all other factors, only length of intervention was related to a significantly higher risk of complications in patients after neoadjuvant chemotherapy, with an OR of 1.15 (1.01–1.31) for SSI and 1.32 (1.15–1.51) for complications according to the Clavien–Dindo classification (ORs and 95% confidence intervals [CIs] from logistic regression).
      Although these results derive from an exploratory analysis, which at least for SSI is only bordering on significance, the results seem to suggest that the risk of SSIs increases 15% per hour of intervention and the risk of complications according to the Clavien–Dindo classification increases 32% per hour of intervention.

      4. Discussion

      Surgical resection plays a major role in the treatment of colorectal liver metastases [
      • Nanji S.
      • Cleary S.
      • Ryan P.
      • et al.
      Up-front hepatic resection for metastatic colorectal cancer results in favorable long-term survival.
      ]. The safety of this procedure has been established, and several studies have reported satisfactory results with the reported 5-y survival rate after initial hepatectomy in the range of 20%–50% [
      • Hasegawa K.
      • Takahashi M.
      • Ohba M.
      • et al.
      Perioperative chemotherapy and liver resection for hepatic metastases of colorectal cancer.
      ].
      Liver metastases can be divided into three categories: (1) resectable, (2) not optimally resectable, and (3) unresectable [
      • Sugihara K.
      • Uetake H.
      Therapeutic strategies for hepatic metastasis of colorectal cancer: overview.
      ,
      • Pestalozzi B.C.
      • Gruttadauria S.
      • Clavien P.A.
      Hepatic arterial infusion: the beginning of the combination era.
      ]. A recent expert consensus statement recommends that neoadjuvant chemotherapy should be done even for metastases that are resectable at the time of presentation [
      • Adams R.B.
      • Aloia T.A.
      • Loyer E.
      • et al.
      Selection for hepatic resection of colorectal liver metastases: expert consensus statement.
      ]. In addition, liver metastases are regarded as not optimally resectable, and chemotherapy is administered first if any of the following conditions are present: four or more metastases; 5 cm or larger metastases; synchronous liver metastases; positive lymph nodes surrounding the primary lesion; tumors adjacent to hepatic veins; and tumors adjacent to the bilateral portal branches. If the chemotherapy is effective, resection is undertaken [
      • Adam R.
      • De Gramont A.
      • Figueras J.
      • et al.
      The oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary international consensus.
      ,
      • Elias D.
      • Baton O.
      • Sideris L.
      • et al.
      Hepatectomy plus intraoperative radiofrequency ablation and chemotherapy to treat technically unresectable multiple colorectal liver metastases.
      ].
      This clinical scenario presents a risk factor for the development of SSIs [
      • Gridelli B.
      • Panarello G.
      • Gruttadauria S.
      • et al.
      Infections after living-donor liver transplantation.
      ] because of a more general susceptibility to infection in patients who have undergone chemotherapeutic treatment and experienced postoperative complications according to the Clavien–Dindo classification, which result from the so-called chemotherapy-associated liver injury [
      • Robinson S.M.
      • Wilson C.H.
      • Burt A.D.
      • et al.
      Chemotherapy-associated liver injury in patients with colorectal liver metastases: a systematic review and meta-analysis.
      ,
      • Brouquet A.
      • Benoist S.
      • Julie C.
      • et al.
      Risk factors for chemotherapy-associated liver injuries: a multivariate analysis of a group of 146 patients with colorectal metastases.
      ,
      • Rubbia-Brandt L.
      • Audard V.
      • Sartoretti P.
      • et al.
      Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer.
      ] and which are brought on by steatosis, steatohepatitis, and sinusoidal obstruction syndrome.
      Despite the presence of considerable evidence to justify the use of adjuvant chemotherapy with oxaliplatin and irinotecan for patients with advanced colorectal cancer [
      • Khan A.Z.
      • Morris-Stiff G.
      • Makuuchi M.
      Patterns of chemotherapy-induced hepatic injury and their implications for patients undergoing liver resection for colorectal liver metastases.
      ], the efficacy of neoadjuvant therapy before the resection of colorectal liver metastases has yet to be proven and remains controversial. An EORTC [
      • Sorbye H.
      • Mauer M.
      • Gruenberger T.
      • et al.
      Predictive factors for the benefit of perioperative FOLFOX for resectable liver metastases in colorectal cancer patients (EORTC Intergroup Trial 40983).
      ,
      • Nordlinger B.
      • Sorbye H.
      • Glimelius B.
      • et al.
      Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial.
      ] (European Organization for the Research and Treatment of Cancer) study of 364 patients randomized to surgery alone or six cycles of FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) found that chemotherapy led to a decrease in the size of lesions on radiologic imaging, which was then confirmed by pathologic examinations of resected specimens. Survival data on these patients indicated that treatment with FOLFOX is associated with better progression-free survival compared with surgery alone. There is also evidence on the benefit of preoperative chemotherapy from studies that used agents to reduce metastases to render them resectable. The first such study, conducted by Bismuth et al. [
      • Bismuth H.
      • Adam R.
      • Lévi F.
      • et al.
      Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy.
      ] in 1996, analyzed 53 patients with colorectal metastases treated with 5-fluorouracil, folinic acid, and oxaliplatin. After chemotherapy, 37 patients underwent major surgery and 16 had minor resections with 3- and 5-y survival rates of 54% and 40%, respectively, indicating that chemotherapy had benefited patients by rendering them candidates for hepatic resection [
      • Lubezky N.
      • Winograd E.
      • Papoulas M.
      • et al.
      Perioperative complications after neoadjuvant chemotherapy with and without bevacizumab for colorectal liver metastases.
      ].
      One limitation of our study is the small sample size in both groups. However, with regard to SSIs and postoperative complications according to the Clavien–Dindo classification in hepatic surgery, there was no statistically significant correlation between the patients who underwent neoadjuvant chemotherapy and those who did not, as reported in Tables 4 and 5. These results are consistent with those from other studies [
      • Kesmodel S.B.
      • Ellis L.M.
      • Lin E.
      • et al.
      Preoperative bevacizumab does not significantly increase postoperative complication rates in patients undergoing hepatic surgery for colorectal cancer liver metastases.
      ,
      • Benoist S.
      • Nordlinger B.
      The role of preoperative chemotherapy in patients with resectable colorectal liver metastases.
      ,
      • Hebbar M.
      • Pruvot F.R.
      • Romano O.
      • et al.
      Integration of neoadjuvant and adjuvant chemotherapy in patients with resectable liver metastases from colorectal cancer.
      ].
      In the 1980s and 1990s, the development of organ/space SSIs after hepatectomy was reported as a fatal complication causing liver failure and death. Although rates of organ/space SSIs after hepatectomy have been reported as ranging from 4.7%–25%, rates of hospital mortality caused by organ/space SSIs have declined [
      • Sadamori H.
      • Yagi T.
      • Shinoura S.
      • et al.
      Risk factors for major morbidity after liver resection for hepatocellular carcinoma.
      ,
      • Campbell Jr., D.A.
      • Henderson W.G.
      • Englesbe M.J.
      • et al.
      Surgical site infection prevention: the importance of operative duration and blood transfusion—results of the first American College of Surgeons-National Surgical Quality Improvement Program Best Practices Initiative.
      ,
      • Fiorio M.
      • Marvaso A.
      • Viganò F.
      • Marchetti F.
      Incidence of surgical site infections in general surgery in Italy.
      ]. Some studies have assessed the effect of multiple factors such as diabetes, obesity, smoking, and liver resection on complications in this type of surgery [
      • Moreno Elola-Olaso A.
      • Davenport D.L.
      • Hundley J.C.
      • Daily M.F.
      • Gedaly R.
      Predictors of surgical site infection after liver resection: a multicentre analysis using National Surgical Quality Improvement Program data.
      ,
      • Rosenberger L.H.
      • Politano A.D.
      • Sawyer R.G.
      The surgical care improvement project and prevention of post-operative infection, including surgical site infection.
      ,
      • Gruttadauria S.
      • Saint Georges Chaumet M.
      • Pagano D.
      Impact of blood transfusion on early outcome of liver resection for colorectal hepatic metastases.
      ].
      Our study found no statistically significant correlation between these risk factors and the incidence of SSIs or complications according to the Clavien–Dindo classification in hepatic surgery for colorectal liver metastases, although multicenter studies would help better define the problem.
      Other variables related to the duration of liver surgery, length of total hospital stay, and length of postoperative hospital stay seem to have some correlation with the SSIs and postoperative complications according to the Clavien–Dindo classification, with P < 0.005 and P < 0.0001, respectively, as reported in Table 5.
      We found that the duration of liver surgery is a risk factor for SSIs, with an OR of 1.15 (CI, 1.01–1.31), and for complications according to the Clavien–Dindo classification, with an OR of 1.35 (CI, 1.17–1.55).

      5. Conclusions

      To sum up, our study found that neoadjuvant chemotherapy is not a significant risk factor for SSIs or complications according to the Clavien–Dindo classification, and that the total length of hospital stay, length of postoperative hospital stay, and duration of liver surgery were independent predictors of SSIs and complications according to the Clavien–Dindo classification.

      Acknowledgment

      The authors would like to thank Warren Blumberg of ISMETT's Language Services Department for his help in revising this article.

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