Abstract
Background:
Outcomes of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) among patients with peritoneal carcinomatosis (PC) depend largely on the extent of peritoneal disease. Since PC is not reliably evaluated with cross-sectional imaging, tumor burden is often evaluated with diagnostic laparoscopy (DLS). The aims of this study are to evaluate the safety of DLS in patients with peritoneal disease and determine if DLS delays time to CRS-HIPEC.
Methods:
We performed an institutional retrospective review of 145 patients who underwent CRS-HIPEC between 2013–2020. Patients were divided into two groups: those who underwent an electively scheduled DLS prior to CRS-HIPEC and those who did not. Intraoperative and postoperative complications associated with DLS were determined from the surgeon’s operative report. Time from diagnosis of PC to CRS-HIPEC were compared between the two groups.
Results:
Of the 145 patients available for analysis, 47% (68) underwent DLS and 44% (64) did not. Of all the diagnostic laparoscopies performed, there was one (1.5%) intraoperative complication. The duration between diagnosis of peritoneal carcinomatosis and surgery was 4.9 months among patients who underwent DLS prior to CRS-HIPEC and 4.3 months among patients who did not (p=0.79).
Conclusion:
In this retrospective analysis, diagnostic laparoscopy prior to CRS/HIPEC demonstrated a comparable rate of DLS-associated complications compared to other gastrointestinal malignancies and does not prolong time from diagnosis to CRS-HIPEC. Thus, in patients undergoing evaluation for CRS-HIPEC, diagnostic laparoscopy provides significant value in patient selection without incurring perioperative risk or delay in CRS-HIPEC.
Introduction
Cytoreductive Surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has emerged as the treatment of choice for patients with peritoneal dissemination of cancer, known as peritoneal carcinomatosis (PC). In patients with PC, outcomes after CRS-HIPEC largely depend on the extent of peritoneal disease as characterized by the peritoneal carcinomatosis index (PCI) and completeness of cytoreduction (CCR). Patients with no residual tumor nodules (CCR 0) or <2.5mm of residual peritoneal disease after cytoreduction (CCR 1) are considered to have a more favorable prognosis than those who did not undergo complete cytoreduction1–3. Thus, strict patient selection is necessary to prevent morbid and nontherapeutic laparotomies in patients who are unlikely to achieve a CCR0 or 1 and confer a survival benefit, which can occur in up to a quarter of patients undergoing CRS-HIPEC4–6. Preoperative cross-sectional imaging can adequately assess extraperitoneal disease or distant metastases but is limited in its ability to detect peritoneal deposits smaller than 5mm6. Several studies have demonstrated that computed tomography (CT) scans do not correlate well with the PCI score during CRS-HIPEC and is inferior to exploratory laparotomy7,8. Other imaging modalities, such as positron emission tomography/CT scans and magnetic resonance imaging (MRI) have not been shown to have increased sensitivity over CT scans in determining extent of disease9,10.
Diagnostic laparoscopy (DLS) has become a widely utilized staging tool for evaluation of other gastrointestinal (GI) tumors and several studies have documented its utility in patients with PC. A single-center retrospective study in 2016 demonstrated that DLS has a positive predictive value of 83% in its ability to predict complete cytoreduction1. Another recent retrospective study noted a significant decrease in the rate of nontherapeutic laparotomies after introduction of preoperative DLS into the institution’s diagnostic algorithm for patients with PC10. Additionally, several studies have demonstrated the correlation between DLS findings and PCI score based on direct visualization5,10–13.
However, it is unclear to what risk these benefits occur. In patients undergoing DLS for pancreatic or gastric cancer, the risk of associated morbidity ranges from 2–4%14,15. Patients with peritoneal carcinomatosis are at potentially increased risk for morbidity associated with DLS since many patients with PC have recurrent cancer and have thus had at least one previous tumor resection. Additionally, pseudomyxoma peritonei, which is mucin accumulation throughout the peritoneum, and peritoneal disease may make laparoscopic abdominal entry and visualization challenging. Additionally, it is unknown if undergoing a DLS prolongs time to CRS-HIPEC due to scheduling constraints, repetitive episodes of general anesthesia, or potential DLS-associated complications. This study aims to evaluate the safety of DLS in patients requiring CRS-HIPEC and determine if CRS-HIPEC is delayed in such patients.
Methods
Data Sources and Definitions
The retrospective study was approved by Institutional Review Board of Vanderbilt University Medical Center (IRB # 200638) and utilizes a prospectively maintained database of all patients with PC who underwent CRS-HIPEC from 2013 – 2021 at Vanderbilt University Medical Center (Nashville, TN). We utilized this database to collect patient demographic information, such as gender, age, race, BMI, state residence, insurance status, American Society of Anesthesiologists (ASA) class, and Eastern Cooperative Oncology Group (ECOG) performance status as well at treatment information. Oncologic data, such as tumor origin, grade, and presence of extraperitoneal metastases were based on final pathology report from the surgical specimen at the time of CRS-HIPEC and from the electronic health record. Additionally, the peritoneal carcinomatosis index (PCI), and complete cytoreduction score (CCR) were obtained from the surgeon’s CRS-HIPEC operative note.
Patients were placed into two groups based on whether they underwent diagnostic laparoscopy prior to CRS-HIPEC to assess disease burden. The DLS group consisted of patients who underwent an electively scheduled DLS that did not occur on the same day as the patient’s resection of primary tumor or day of CRS-HIPEC. The NO DLS group consisted of patients who did not undergo an electively scheduled DLS at all during the diagnostic process. Patients who underwent a DLS at the time of CRS-HIPEC or at the time of primary resection were excluded from the analysis. We examined the operative notes and progress notes from patients in the DLS group to assess for associated complications, which included intraoperative enterotomy or serosal injury, anesthesia-related complications, postoperative hernia, surgical site infection, deep venous thrombosis, or urinary tract infection. We then compared time to CRS-HIPEC between the two groups, which was defined as months from diagnosis of PC to CRS-HIPEC.
Statistical Analysis
Demographic, oncologic, and clinical factors were compared based on DLS grouping. Categorical variables are recorded as percentages and compared using Chi-squared test, and continuous variables are recorded as means and compared using Kruskal-Wallis test. All analyses were performed using IBM Statistical Product and Service Solutions for Mac, Version 27 (IBM Corp., Armonk, N.Y., USA) software package and statistical significance was set at p=0.05.
Results
Patient Characteristics
We identified 145 patients who underwent CRS-HIPEC from 2013 – 2020 at our institution, 47% (68) of whom underwent an electively scheduled DLS as part of their preoperative workup. There were no significant differences in baseline medical comorbidities or demographics, except for insurance status. Patients in the NO DLS group were significantly more likely to be uninsured compared to the patients in the DLS group (18.7% vs 2.5%; p=0.001). Patients in both groups had similar functional statuses as evidenced by similar ASA classes and ECOG performance status scores. Notably, patients in each group underwent a similar number of previous abdominal surgeries (DLS 1.6 vs NO DLS 1.7, p=0.93) and had similar primary tumor types. The most common tumor was appendiceal in both groups (DLS 56.8% vs NO DLS 59.3%, p=0.74) followed by colorectal (DLS 26% vs NO DLS 32.8%, p=0.34). However, patients who underwent DLS prior to CRS-HIPEC had an increased incidence of high-grade disease (34.2% vs 16.5%, p=0.03) and presence of extraperitoneal metastatic disease (16% vs 8%, p= 0.04). Despite these differences, patients in both groups underwent neoadjuvant chemotherapy at similar rates (DLS 38.2% vs NO DLS 24.5%, p=0.08) and for similar durations (DLS 4.9 months vs NO DLS 4.5 months, p=0.79). Notably, patients in the DLS group had similar PCI scores (14.2 ± 4.3 vs 14.7 ± 4.1, p=0.64) but higher rates of complete cytoreduction (85% vs 67%, p=0.03) than patients in the NO DLS group. Patient demographic, medical, and oncologic characteristics are detailed in Table 1.
Table 1:
Patient Baseline Characteristics based on Diagnostic Laparoscopy Status
| Variables | DLS % (n) | NO DLS % (n) | p Value |
|---|---|---|---|
| Total | 47% (68) | 44% (64) | |
| Gender | 0.19 | ||
| Male | 54.3% (37) | 42% (27) | |
| Female | 45.7% (31) | 58% (37) | |
| Age (mean ± std) | 54.3 ± 8.5 years | 52.4 ± 10.5 years | 0.73 |
| Race | 0.85 | ||
| White | 82.7% (56) | 89% (57) | |
| African-American | 14.4% (10) | 9.4% (6) | |
| Other | 2.9% (2) | 1.6% (1) | |
| BMI (mean ± std) | 28 ± 5.9 | 29.5 ± 5.7 | 0.88 |
| Insurance Status | 0.001 | ||
| Private | 81.5% (55) | 75% (48) | |
| Public | 16% (11) | 6.3% (4) | |
| Uninsured | 2.5% (2) | 18.7% (12) | |
| In-State Residence | 65.4% (44) | 70% (45) | 0.77 |
| ASA Class | 0.19 | ||
| 1 | 2.5% (2) | 0% (0) | |
| 2 | 24.5% (17) | 6.4% (10) | |
| 3 | 69.1% (47) | 82.8% (53) | |
| 4 | 2.9% (2) | 11.8% (2) | |
| ECOG Performance Status | 0.81 | ||
| 0 | 28.4% (20) | 31.2% (20) | |
| 1 | 37% (26) | 32.8% (21) | |
| 2 | 1.3% (1) | 1.6% (1) | |
| 3 | 1.3% (1) | 1.6% (1) | |
| Number of Previous Abdominal Surgeries | 1.6 ± 1.4 | 1.7 ± 1.3 | 0.93 |
| Peritoneal Surface Disease Severity Score (mean ± std) | 9.8 ± 4.3 | 12.2 ± 5.4 | 0.19 |
| Charlson Comorbidity Index (mean ± std) | 7.6 ± 1.6 | 7.1 ± 1.1 | 0.44 |
| Synchronous Disease | 79% (53) | 75% (48) | 0.66 |
| Primary Tumor Origin | 0.55 | ||
| Colorectal | 26% (18) | 32.8% (21) | 0.34 |
| Appendiceal | 56.8% (39) | 59.3% (38) | 0.74 |
| Peritoneal Mesothelioma | 7.4% (5) | 4.7% (3) | 0.19 |
| Ovarian | 6.2% (4) | 4.7% (3) | 0.65 |
| Other | 2.9% (2) | 1.6% (1) | 0.66 |
| Tumor Grade | 0.03 | ||
| Low Grade | 52.6% (38) | 65.5% (40) | |
| Intermediate Grade | 13.2% (9) | 18% (11) | |
| High Grade | 34.2% (21) | 16.5% (10) | |
| Presence of Extraperitoneal Metastases | 16% (11) | 8% (6) | 0.04 |
| Neoadjuvant Chemotherapy | 38.2% (26) | 24.5% (15) | 0.08 |
| Duration of Neoadjuvant Chemotherapy | 4.9 ± 1.7 months | 4.5 ± 1.5 months | 0.79 |
| Peritoneal Carcinomatosis Index Score (mean ± std) | 12.0 ± 4.3 | 16.7 ± 4.1 | 0.04 |
| Completion of Cytoreduction Score | 0.03 | ||
| 0 | 85% (58) | 67% (43) | |
| 1 | 13.5% (9) | 26.6% (17) | |
| 2 | 1.5% (1) | 6.3% (4) |
DLS-Associated Complications and time to CRS-HIPEC
Among those who underwent DLS prior to CRS-HIPEC, only one patient (1.5%) sustained a DLS-associated complication. The sole complication was a serosal injury that was identified at the time of DLS and closed primarily. The patient did not have any prolonged sequalae of this injury. Additionally, this patient underwent CRS-HIPEC approximately 5 months after diagnosis of peritoneal carcinomatosis, near the average of 4.7 months seen in the DLS group. Although not included in our analysis, 1 of 16 patients (6.3%) who underwent DLS at the time of repeat CRS-HIPEC sustained an enterotomy open laparoscopic access, which was identified and eventually resected as part of the cytoreduction that ensued. No other DLS-associated complications occurred.
On average, patients in the DLS group underwent CRS-HIPEC 4.9 months after their diagnosis of peritoneal carcinomatosis, while patients in the NO DLS group underwent CRS-HIPEC 4.3 months after diagnosis of PC (p=0.79). DLS-associated morbidity and time to CRS-HIPEC for each group is displayed in Table 2.
Table 2:
DLS-Associated Morbidity and Time to CRS-HIPEC
| Variables | DLS % (n) | NO DLS % (n) | p Value |
|---|---|---|---|
| DLS-Associated Complications | 1.5% (1) | 0% (0) | 0.54 |
| Time to CRS-HIPEC (mean ± std) | 4.9 ± 2.2 months | 4.3 ± 1.9 | 0.79 |
Discussion
This present study demonstrates that laparoscopy is a safe diagnostic measure in patients with peritoneal carcinomatosis and does not delay definitive CRS-HIPEC. Despite the concern that patients with PC may present challenges with safe laparoscopic access due to disease burden and increased number of prior abdominal operations, only one serosal injury occurred in the DLS group. Furthermore, the only other laparoscopic access injury occurred during DLS at the time of repeat CRS-HIPEC for a patient with recurrent PC. Between 2–4% of patients undergoing DLS for other gastrointestinal malignancies, such as gastric or pancreatic cancers, may sustain an associated complication, which is higher than observed in our patient cohort14,15. However, our data indicate a significantly increased risk of bowel injury in this patient cohort compared to all patients undergoing diagnostic laparoscopy, with an incidence of less than 1%16. It should be noted that the patient who sustained an iatrogenic serosal injury during DLS did not have a significant delay in timing of CRS-HIPEC. Thus, surgeons performing CRS-HIPEC should not forego diagnostic laparoscopy for fear of potential complication given the well documented benefit of preventing nontherapeutic laparotomies and minimal risk.
In our patient cohort, several interesting trends emerged. Despite having similar demographic characteristics and medical comorbidities, patients who did not undergo preoperative DLS were more likely to be uninsured compared to patients in the DLS group. Several studies have demonstrated that privately insured patients with cancer, including gastrointestinal malignancies, have improved survival compared to patients with no insurance are likely to receive treatment sooner17,18. Specifically, among uninsured cancer patients, significant delays in access to care and completion of recommended therapy have detrimental effects on prognosis and cancer-related survival19,20. While our study does not correlate insurance status with ability to undergo DLS, insurance status is generally viewed as a surrogate for other socioeconomic factors. Thus, lack of insurance may be one of many increased barriers to healthcare that uninsured patients face. Additionally, it is unknown if patients were reluctant to undergo DLS given their necessity to self-pay.
Other significant differences in our patient cohort include key oncologic characteristics: patients who underwent DLS had higher incidences of extraperitoneal metastases and high-grade primary tumors, both of which are indicative of more aggressive disease. However, these patients had similar PCI scores compared their counterparts. This suggests a potential selection bias among surgeons when determining who should undergo a preoperative DLS prior to CRS-HIPEC. DLS is not performed routinely at our institution and is thus dependent on surgeon discretion. Based on the noted differences between the two groups, the surgeon is likely to recommend DLS in the presence of more aggressive disease, such as high-grade disease, extraperitoneal metastases, or anticipated PCI based on cross-sectional imaging. These patients are more likely to have increased PCI and thus may be less likely to undergo complete cytoreduction. While this study was not designed to evaluate for patient selection for CRS-HIPEC based on DLS findings, the fact that the DLS group had similar PCI scores despite higher rates of high-grade and distant metastases indicate that DLS was able to filter out patients who would otherwise not be a suitable candidate for CRS-HIPEC. Consequently, patients in the DLS group underwent complete cytoreduction significantly more often than patients who did not undergo DLS. Notably, a CCR2 resection was approximately 4x more likely to occur in the NO DLS group compared to the DLS group (6.3% vs 1.5%). These findings demonstrate the benefit of DLS in its ability to select appropriate CRS-HIPEC candidates, namely those who are more likely to undergo complete cytoreduction.
A potential critique of performing DLS prior to CRS-HIPEC is that it delays time to CRS-HIPEC due to operative scheduling and patient recovery. Our data does not support this claim as patients in both groups underwent CRS-HIPEC at similar time points relative to their diagnosis of peritoneal carcinomatosis. While several studies have documented the benefit of CRS-HIPEC, this is the first study to evaluate such benefits in the context of associated morbidity and time from diagnosis to CRS-HIPEC.
This study should be understood in the context of its retrospective nature and inherent selection bias. While this is a relatively large cohort for this patient population, our data includes only patients who underwent CRS-HIPEC and excludes patients with peritoneal carcinomatosis who underwent DLS but not CRS-HIPEC or those who underwent an aborted CRS-HIPEC. Thus, the patients in the DLS group are reflective of a patient population that is least likely to experience a DLS-associated injury and most likely to successfully undergo complete cytoreduction. Thus, the low incidence of DLS-associated morbidity may be higher in all patients undergoing DLS as part of their diagnostic workup than demonstrated in this patient cohort.
This retrospective study of a large cohort of patients with peritoneal carcinomatosis who underwent CRS-HIPEC demonstrates that preoperative DLS is safe, with rates of morbidity similar to DLS performed in the setting of other GI malignancies. Additionally, we demonstrate that preoperative DLS does not delay CRS-HIPEC from the time of diagnosis of peritoneal carcinomatosis.
Key Take-Aways.
Diagnostic laparoscopy in the setting of peritoneal carcinomatosis is safe, with a similar morbidity rate to other gastrointestinal malignancies.
Diagnostic laparoscopy to evaluate degree of peritoneal carcinomatosis does not delay cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.
Acknowledgements
We would like to acknowledge our funding source, the National Cancer Institute (T32CA106183).
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Institutes of Health – National Cancer Institute T32CA106183.
Footnotes
Declaration of Conflicting Interests
The Authors declare that there is no conflict of interest.
Disclosures: None
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