The impact of surgical staging in patients with colorectal peritoneal metastases scheduled for CRS-HIPEC

Introduction

The peritoneum is the third most common location of metastases from colorectal cancer with an incidence of around 8 %, occurring equally in a synchronous or metachronous situation [1]. The standard treatment of isolated peritoneal metastases is cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) [2], 3]. However, the prognosis is largely dependent on the extent of peritoneal spread as measured with the peritoneal cancer index (PCI) [4], 5]. Preoperative work up includes abdominal computed tomography in order to give a rough estimate of the extent of peritoneal growth, and in borderline cases, a surgical staging procedure, i.e. laparoscopy or laparotomy is used to more precisely assess the PCI [6], but few studies have evaluated the value of surgical staging procedures as a tool to select patients for CRS-HIPEC.

One limitation associated with diagnostic laparoscopy is incomplete preoperative surgical staging, which occurs in around 20 % of the cases, mostly due to adhesions after previous surgery. This results in incomplete visualization of the abdominal regions and thereby limits the selection of patients eligible for CRS-HIPEC [7]. Furthermore, tumour cell entrapment resulting in port site metastases might occur after laparoscopy. However, laparoscopy is considered a safe and feasible procedure for staging peritoneal metastases and negligible surgical complications have been reported [8]. Staging laparotomy is a more invasive procedure and is also associated with a risk of tumour entrapment in the abdominal wall incision.

Our study aimed to assess the prognostic impact of surgical staging procedures in patients with peritoneal metastases scheduled for CRS-HIPEC with respect to overall and recurrence-free survival, frequency of abdominal wall metastases, and proportion of inoperability (open and close). In the assessment, staging procedures performed on purpose were considered separately. A secondary aim was to compare the PCI at the staging procedure with that recorded at the definite CRS-HIPEC procedure.

Methods

Patients and data collection

Patients with a histopathologically verified colorectal cancer with peritoneal metastases scheduled for a primary CRS and HIPEC procedure were included. Data were collected from patient records and a prospectively maintained HIPEC register. We registered: age, gender, location of primary tumour, type of treatment (CRS-HIPEC, CRS only, debulking or laparotomy only because of inoperability, hereafter named open-close), HIPEC-regimen, peritoneal cancer index (PCI), completeness of cytoreduction (CC) score [9], [10], [11], neoadjuvant treatment, surgical staging procedure with laparotomy or laparoscopy or alternatively staging of the peritoneal metastases during elective or emergency surgery, resection of abdominal wall at definite CRS-HIPEC, postoperative histopathology in peritoneal specimens and the abdominal wall, and presence of signet ring cells.

The surgical staging group were categorised into four groups; discovery of peritoneal metastases during emergency surgery mostly due to intestinal obstruction; during primary tumour surgery with unexpected finding of peritoneal metastases; decisions made during multidisciplinary team meeting for a surgical staging procedure requested by the HIPEC centre; and lastly findings of peritoneal metastases during other procedures such as cholecystectomy, liver or hernia surgery.

To ensure a more homogeneous cohort and facilitate comparison between staged and non-staged patients, only patients who had undergone a surgical staging procedure requested by the HIPEC-centre (n=32) were included in this study, yielding a total of 138 patients (Figure 1). The staging group consisted of patients who had undergone staging at a referral hospital with expertise in colorectal surgery, though the exact experience of the referral hospital experience was not recorded.

Figure 1:

Flow-chart of the study cohort.

Surgical staging procedure were requested by the HIPEC centre for patients deemed suitable for staging based on radiological finding, including those without extensive adhesions but with radiological suspicion of significant tumor growth, possible small bowel involvement or advanced tumor growth in regions involving pancreas, stomach or hepatic pedicle.

The surgical staging procedure was performed either as laparoscopy or mini-laparotomy, before or after neoadjuvant therapy, depending on the radiological findings. Although the radiological PCI score is not routinely documented at our centre, staging was primarily indicated for cases where CT imaging suggested a PCI score greater than 15.

All patients were discussed in a multidisciplinary team meeting before being considered eligible for CRS-HIPEC. Patients with good performance status, age <80 years, few comorbidities or limited tumor extent on the CT-scan were considered CRS-HIPEC.

Information about previous staging laparoscopy or laparotomy was registered from referral notes, including PCI score at the staging procedure and whether there was small bowel involvement.

Information on survival was obtained from the Swedish Population Register and all observations were censored in December 2020.

The study was approved by Uppsala County´s Ethics Committee, DnR 2013/203.

Results

Surgical results

The intraoperative PCI score was higher in patients who had undergone a surgical staging procedure than in the group of patients without a staging procedure before CRS-HIPEC (p<0.001, Table 1). The median PCI score at definite surgery was higher compared to what was recorded at the surgical staging procedure, especially in those who had undergone a staging laparoscopy (Figure 2). The proportion of patients in whom radical surgery was performed was higher in the group without a staging procedure but the difference was not significant (p=0.084, Table 1).

Figure 2:

Distribution of median PCI-score registered at staging procedure and at definite CRS-HIPEC.

In all, 36 patients underwent abdominal wall resection during definite CRS-HIPEC surgery, of whom 8 had verified port site recurrence and none with recurrences in the abdominal incision. In total, 25 patients had no histopathological malignancy in the abdominal wall and 102 patients had no clinical sign of abdominal wall recurrences detected during the definite CRS-HIPEC surgery, and therefore no abdominal wall resection was performed.

Abdominal wall recurrences were more common after a staging procedure (8/32, 25 %) compared to cases with no staging surgery (3/106, 3 %) before CRS-HIPEC (p<0.001, Table 1). The probability of abdominal wall recurrence was higher in the surgical staging group (OR 10.26; p=0.004 (Table 2).

Table 2:

Logistic regression analysis of probability for abdominal wall recurrences.

Variable, n	OR	p-Value	95 % CI
Age
≥ 66 years	10.1	0.051	0.99–103.4
Gender
Woman	1.77	0.480	0.37–8.56
Metachronous	1.45	0.695	0.23–9.08
Neoadjuvant chemotherapy
Yes	1.35	0.738	0.23–7.77
Surgical staging
Yes	10.26	0.004	2.11–49.87
PCI score at definite CRS-HIPEC surgery
>20	1.36	0.756	0.19–9.63
Presence of signet ring cells
Yes	0.46	0.421	0.07–3.02

1. OR, odds ratio; CI, confidence interval.

Discussion

Our study evaluated the value of preoperative surgical staging in patients with peritoneal metastases from colorectal cancer eligible for CRS-HIPEC. This question is not only important for surgeons who specialize in CRS-HIPEC but also for surgeons referring patients to a CRS-HIPEC centre. Staging laparoscopy has long been considered a valuable tool for assessing the extent of peritoneal tumours and predicting whether complete cytoreduction is achievable [6]. We found that 25 % of the patients were inoperable at definite surgery after undergoing preoperative surgical staging, mainly due to widespread peritoneal metastases with a PCI >20. These findings align with those of Iversen et al. reported, who reported that 10 out of 27 patients were ineligible for CRS-HIPEC due to advanced tumour growth in difficult-to-assess regions, such as the pancreas, hepatic pedicle, and ureters, despite prior staging laparoscopy. These regions are challenging to evaluate laparoscopically, highlighting the limitations of staging laparoscopy in certain cases [7].

At our center, 72 % of patients completed CRS-HIPEC, while 3 % underwent CRS only after a preoperative staging procedure requested by the HIPEC-center. These results are in agreement with the results of Iversen et al. Over the past decade, we have routinely employed laparoscopy in the preoperative diagnostic assessment of selected patients with peritoneal metastases from colorectal and appendiceal cancer. This is particularly useful when radiological staging is uncertain or when assessing small bowel involvement is crucial for predicting the possibility of complete cytoreduction. Patient selection for surgical staging procedure is typically driven by the limitations of radiological assessments.

While radiological staging can guide decision-making, particularly when signs of obstruction or ascites suggest advanced disease, it often fails to fully capture the extent of peritoneal dissemination, especially involving the small intestine. Laparoscopy provides better visualization, making it valuable when CT scan show borderline PCI-scores [14]. However, non-invasive modalities might be preferable. A Dutch multicentre randomized controlled trial is currently investigating the role of MRI as a preoperative tool for predicting eligibility for definite surgery and its potential to reduce the need for surgical staging [15].

Despite the widespread use of PCI score by Swedish colorectal surgeons, our study found that the PCI score was not recorded in 19 of 32 patients (59 %) during the surgical staging procedure. Additionally, these evaluations were not performed or supervised by a HIPEC specialist, which may have influenced the accuracy of staging. This issue is particularly relevant in less experienced centers, where patients with higher PCI scores may be selected for CRS-HIPEC, potentially leading to suboptimal treatment decisions and influencing the overall outcomes. The lack of standardized PCI documentation in staging may have led to inconsistencies, highlighting the need for training and collaboration in centers with less expertise in peritoneal metastasis management.

The median time interval between the staging procedure to definitive surgery was 52 days. Patients with longer intervals often received neoadjuvant therapy or experienced delays due to holiday variations. A separate analysis revealed that the lead time was shorter when staging laparotomy was performed. We also observed that the reporting of PCI scores were more consistently reported in the later period of the study, suggesting that national educational efforts may have improved over time.

When comparing laparoscopy with laparotomy for preoperative staging, we found that the estimated PCI score reported by laparoscopy was higher at CRS-HIPEC, while laparotomy showed less discrepancy. This may be due to the more extensive abdominal exposure provided by laparotomy. However, laparotomy is often performed for cases with adhesions and is associated with longer recovery compared to diagnostic laparoscopy. Laparotomy may be a more effective staging technique when performed by non-HIPEC surgeons in local hospital settings. Alternatively, the use of hand-port assistance during laparoscopy could improve the accuracy of PCI determination.

One of the challenges identified in our study was the disparity between staged and non-staged patients. This likely reflects the fact that surgical staging is more commonly offered to patients with synchronous peritoneal metastases, often before the initiation of neoadjuvant treatment. A higher PCI-score at definite CRS-HIPEC might also reflect a more aggressive tumor biology or host related factors that trigger an increase in peritoneal dissemination [16]. Consequently, the characteristic biological factors of these patients may impact outcomes in ways that are not fully captured by radiological staging or PCI alone.

Another limitation of surgical staging procedures is the difficulty in adequately visualizing the extent of peritoneal metastases in regions affected by adhesions or large tumour masses. However, laparoscopic evaluation performed at a HIPEC centre may be more effective in selecting patients eligible for CRS-HIPEC; minimizing the risk of incomplete cytoreduction, optimizing patient selection, and reducing delays in initiating palliative oncological therapy for patients with extensive disease [7]. Given that operating resources may limit the availability of laparoscopic evaluation at HIPEC centers, educating surgeons in local and regional hospitals may improve the reliability of local staging procedures.

Concerns about port site metastases after laparoscopic surgery have been raised since the procedure´s introduction, with early studies reporting an incidence of 21 %. Nowadays, current rates are below 1 %, similar to the incidence of wound metastases after open surgery [17]. In our cohort, port site recurrences following laparoscopy was 25 %, while no cases of abdominal wall scar recurrences were observed after laparotomy. The significantly higher risk of port site recurrence after previous surgical staging with laparoscopy in patients with peritoneal metastases underscores the need for awareness of the occurrence of abdominal wall recurrences after surgical staging procedures. This findings emphasize the importance of midline port placements, as these sites can easily excised during CRS-HIPEC, and by evacuation of the intraabdominal gases through the trocars before removal, thereby avoiding tumour cells entrapment in the port sites [18]. The potential mechanisms behind the relatively higher rate of abdominal wall recurrences in staged patients suggests that further investigation is needed to determine whether surgical staging itself increases the risk of recurrence. Future research should explore the impact of different staging methods on postoperative outcomes and pattern of metastasis. Based on our observations, we strongly recommend the removal of abdominal midline scars and port sites in cases where recurrences are suspected, either clinically or radiologically.

The incidence of complications with laparoscopic staging has been reported as low in other studies. Valle et al. used video laparoscopy to stage 197 patients with peritoneal metastases, completing full laparoscopic PCI assessments in 196 cases, with only a 2 % complications rate, such as trocar site infection, diaphragm perforation and intraoperative bleeding. Neither Valle nor Iversen reported port site metastases [6], 7]. In general, most of the staging procedures in our cohort were performed at the referral hospitals, and no serious complications were reported, and neither were information on patients considered ineligible for CRS-HIPEC during the staging procedure. Nonetheless, some studies have confirmed the safety and accuracy of diagnostic laparoscopy for patients with peritoneal metastases [19], [20], [21]. Therefore, our primary aim was to evaluate the benefit of staging laparoscopy and laparotomy in selecting patients eligible for CRS-HIPEC, particularly in assessing small bowel involvement. While the use of a separate surgical staging procedure should be selectively considered, the increased risk of abdominal wall recurrences and potential underestimation of peritoneal metastasis extent, particularly during laparoscopy, must be carefully weighed.

A study by Nunez reported a 34 % port site recurrence rate after staging laparoscopy in patients with peritoneal metastases from gastrointestinal, mesothelial, and gynecological origins prior to CRS-HIPEC. Port site recurrence was independently associated with worse overall survival [22]. While we did not find a negative survival impact from abdominal wall recurrences, factors such as PCI ≥21, open & close procedures, and the presence of signet ring cells were independently associated with worse survival. However, we did not account for potential confounders such as differences in surgical techniques, tumor biology, or postoperative care, which could have influenced outcomes.

Many centers routinely resect abdominal wall or port sites during CRS-HIPEC, regardless of pre- or intraoperative evidence of tumour involvement in the abdominal wall [22]. Based on our findings, we believe that surgeons should be aware of the risk of abdominal wall recurrences when considering diagnostic staging with laparoscopy or laparotomy.

Limitations

Despite the valuable insights provided by this study, several limitations exist. Its retrospective design, missing data on key variables, unmeasured confounding factors, and the small sample size of the staged group limit the statistical power and generalizability of our findings. Moreover, the PCI score was not recorded in many staging procedures, and factors associated with aggressive disease may have contributed to the increased risk of abdominal wall recurrences in the staged group. Selection bias may have been a factor, as patients who underwent staging likely had a higher disease burden. Future studies should aim to include larger patient cohorts, ideally through multicenter collaboration, to enhance the generalizability of our findings and control for selection bias by using statistical methods like propensity score matching. Although our study did not address postoperative complications, quality of life, or long-term oncological outcomes, these factors are crucial for assessing the clinical benefits of preoperative surgical staging in selecting patients for CRS-HIPEC.

Conclusions

Our study demonstrates that patients undergoing staging laparoscopy or laparotomy experience no negative impact on overall survival or time to recurrence, although there is an increased risk of abdominal wall recurrences. The higher number of ineligible patients for CRS-HIPEC in the surgical staging group may reflect confounding by indication, with these patients likely having more aggressive tumour biology and higher PCI scores. Imaging-based strategies could offer valuable insights into whether surgical staging is the most effective approach, or if less invasive methods could provide similar diagnostic accuracy with fewer associated risks. Future research should explore these alternative methods to ensure the optimal strategy for staging patients with colorectal peritoneal metastases.