Increased risk for incisional hernia following cytoreductive surgery with hyperthermic intraperitoneal chemotherapy

The incidence of incisional hernias (IH) after midline laparotomy varies from 11% to 20%. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS‐HIPEC) is potentially prone to hernias because a Xiphoid to pubis laparotomy incision performed on patients who have undergone previous abdominal surgeries with the addition of chemotherapy and its related adverse effects.


Introduction
][3][4] Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is potentially prone to hernias because it is a Xiphoid to pubis incision performed on patients who have undergone previous abdominal surgeries with the addition of chemotherapy and its related adverse effects (2).][7][8] Based on our clinical experience, the rates of IH after CRS-HIPEC were much higher than previously reported.The aim of this study was to evaluate the rate of IH after CRS-HIPEC and its risk factors.

Methods
We performed a retrospective review on a prospectively maintained database of 336 patients who underwent CRS-HIPEC in a single institution during March 2015-July 2020.The study was approved by the institutional review board (SMC 16-3715).
We included only patients who underwent combined cytoreduction and HIPEC and had at least 6 months of postoperative follow-up with evaluable postoperative cross-sectional imaging (computed tomography (CT) or Magnetic resonance imaging (MRI)).A total of 336 patients underwent cytoreductive surgery, 135 were excluded (detailed in consort chart, Fig. 1), and 201 patients were eventually included in the study.Postoperative CT and MRI scans were analysed for a presence of IH by a boardcertified radiologist (Z.K).The type and classification of the hernia was determined by the European hernia society (EHS) classification. 9All postoperative complications were reported using the Clavien-Dindo classification. 10

Surgical technique
All HIPEC procedures following cytoreductive surgery were performed according to established protocols using closed-abdomen technique.Xiphoid-Pubis laparotomy with resection of all previous surgical scars, resection of the umbilicus and primary survey for assessment of operative peritoneal cancer index (PCI) was performed. 11All areas of visible metastatic disease were resected, and peritonectomy procedures were performed.At the end of the cytoreduction procedure, completeness of cytoreduction was assessed.HIPEC was added only in cases of complete CRS with completeness of cytoreduction score (CC) of 0 or 1. HIPEC was done using the Performer HT system (Rand-biotech, Medolla, Italy).After completion of cytoreduction, inflow and outflow catheters were inserted: two inflow catheters on the liver surface and three outflow drains in each subphrenic space and in the pelvis.After the catheters were inserted, the fascia was closed with interrupted PDS 1 sutures and subsequent skin closure.The abdomen was perfused with 3000 mL 0.9% NaCl solution or Dextrose 5% water (D5W) depending on the drug protocol used during HIPEC.

Statistical analysis
All the statistical analyses were carried out using SPSS version 25.0 (SPSS Inc., Chicago, IL) software.To test normal distribution for continuous variables, the Kolmogorov-Smirnov test was performed.If normality was rejected, nonparametric tests were used.To test differences in continuous variables between hernia groups, the independent-samples t-test or the Mann-Whitney test was performed.For comparison of dichotomous or categorical variables, the Pearson chi-squared test was performed.Continuous variables are presented as means AE SD and dichotomous/categorical variables as proportions.Univariate and multivariate logistic regression models were performed to assess the risk factors for IH.All statistical analyses were two sided with a significance level of P < 0.05.

Results
We identified 201 patients who underwent a CRS-HIPEC in a single institution and had at least 6 months of follow-up (median 1.8 AE 1.3 years).The average age of the patients was 58.5 AE 12.6; 57.6% of the patients were female.The baseline characteristics and intra-operative specifications are described in Tables 1 and 2 respectively.The average length of stay after surgery was 13.9 AE 10.9 days.The overall complications rate was 53.2% (n = 107).Most of the complications (36.3%, n = 73) were minor (Clavien Dindo score of I-II) mostly surgical site infections, ileus and isolated abdominal collections.Thirty-one patients (15.5%) developed major complications mostly related to anastomotic leak (n = 16, 7.8%) and intra-abdominal collections.A patient was characterized as having an incisional hernia if a hernia was detected and noted on physical exam and/or was present of cross-sectional imaging.The last cross-sectional imaging study of the patient was independently reviewed by an experienced radiologist.
The rate of IH after CRS-HIPEC was 26.9%, 54 patients out of 201.The major risk factors for IH in multivariate analysis were higher American society of Anesthesiologists score (ASA) (OR 3.9, P = 0.012, 95% CI 1.3-11.3),increasing age (OR 1.06, P = 0.004, CI 1-1.1) and increasing BMI (OR 1.1, P = 0.006, CI 1-1.2).No significant differences were observed in terms of the occurrence of incisional hernia based on the primary source of malignancy.Among the 127 patients with colorectal cancer (CRC), 34 individuals had hernia (26.8%).Similarly, 11 out of 38 patients Incision hernias following CRS-HIPEC 2193 with appendiceal malignancy had hernia (28.9%), and 5 out of 11 patients with ovarian cancer had hernia (45.4%).In addition, one patient out of 12 with mesothelioma and three out of 13 patients in the 'other' malignancies group had hernia (23.1%).Furthermore, no significant differences were found in relation to the intraoperative PCI (P = 0.135) and the duration of surgery (P = 0.847).The hernia sites were classified based on EHS classification for IH, 79% of the hernia sites were median (n = 49).The median hernia was mostly at the umbilical level in 58.9% (n = 26) of the patients.Eleven patients (20.4%) had lateral IH secondary to previous stoma sites and large drain sites.Out of all the IH patients, 16 (30.8%)patients had a minor size hernia defect (< 4 cm), 24 patients (46.2%) had moderate size hernia (4-10 cm) and 12 (23.1%)patients had a large hernia.Three patients developed loss of domain (5.6%).Five out of 54 patients with IH (9.3%) necessitated surgical repair for their hernia defect, four patients underwent urgent repair due to incarcerated IH and one patient due to chronic infection of mesh and recurrent hernia after CRS-HIPEC with primary abdominal wall reconstruction.

Discussion
CRS-HIPEC is potentially prone to hernias surgical intervention.6][7][8] This study presents the rates of IH and its risk factors in a cohort of 201 patients after CRS-HIPEC.
The baseline characteristics of this study reflect previous reports in the age, gender and BMI of the participants, 5-7 however, differ in the primary malignancy type and preoperative peritoneal carcinomatosis index (PCI). 5,7Most of the patients in this study (63.2%) were operated due to colorectal carcinoma with relatively high average PCI score (11.4).][14][15][16] As far as we know, so far five studies have examined the rate of IH after CRS-HIPEC: Ravn et al. 6 and Cacales Campos et al. 7 reported a 9-10% incidence at 5 year follow-up.Struller et al. 8 reported a 7% rate of IH with a major risk factor being the type of primary malignancy Pseudomyxoma Peritonei (PMP) or Mesothelioma (probably resemble higher PCI levels).Tuttle et al. reported higher incidence rate of IH À17%, with age, female gender and higher BMI as major risk factors.
In our clinical experience, we have noted that the actual IH rate is higher than previously reported, and that our data is more representative of the real-world experience with IH after CRS-HIPEC.Interestingly, when evaluated based on clinical exam and IH-related complaints only, we were able to identify only 8.9% of the IH.This rate was more than doubled when a radiologist analyzed the presence of IH based on surveillance cross-sectional imaging.Noteworthy, the fascial closure in all the patients in this cohort was performed with continuous loop PDS 1 suture.The IH preserving practices of small bites sutures 14 and mesh augmentations 16 were not yet implemented in those patients, hence affecting the relatively high IH rate.
It is noteworthy that significant factors known to contribute to hernia development, such as primary histopathology, surgery duration, intraoperative PCI, prior surgeries, anastomotic leak, dehiscence, and surgical site infections, did not show a significant impact on hernia occurrence in our regression models.][19] CRS-HIPEC has traditionally included routine excision of the umbilicus and previous fascial scars.In our practice, we generally adhere to these guidelines, particularly in cases where the patients have a higher PCI or if the origin of the cancer is appendiceal or mesothelial.This practice has been further supported by a recent study conducted by Sakata et al., which revealed that 30% of patients with appendiceal peritoneal carcinomatosis had tumour infiltration in the umbilical region. 20ost of the patients who developed hernia in our cohort suffered from a large midline IH which was at the level of the resected umbilicus 46.3% (n = 25).Although this finding is not unusual, as the umbilicus is the weakest point of the abdominal wall, 21 the resection of the umbilicus during CRS may have contributed to this high rate of para-umbilical hernias as well.In addition, 11% of the patients developed lateral hernias.Most of those hernias were in the previous stoma sites, however, four patients (1.7%) developed unique hernias in the subcostal and para-iliac sites secondary to the large infusion HIPEC drains inserted in those areas.
Our policy is to minimize surgical interventions for hernia repairs in patients with IH after CR-HIPEC.However, percentage of the patients necessitated surgery due to hernia-related complications.
In conclusion, based on our data, IH is a common sequela of CRS-HIPEC that occurs in more than 25% of the patients.
The limitations of this study include those inherent to its retrospective design.
In addition, due to technical limitations in the electronic medical record software, no data was available for the smoking status of the patients.
The strengths of this study lie in its design as a single institution study, where all procedures and abdominal fascial closure were performed by the same team and the data was gathered prospectively by both clinical and radiological parameters.
We believe this data represents the more real-world incidence of IH after CRS-HIPEC and reinforces previous data regarding the risk factors contributing to it.More research is needed to find the appropriate intraoperative interventions to minimize this sequela.

Disclosure statement
To the best of our knowledge, there are no financial or personal stakes or convictions that might compromise the impartiality of this study.

Table 1
Baseline characteristics †Not including perfusion time.